EP1781263B1 - Medicament in a multilayer form - Google Patents

Medicament in a multilayer form Download PDF

Info

Publication number
EP1781263B1
EP1781263B1 EP05746448A EP05746448A EP1781263B1 EP 1781263 B1 EP1781263 B1 EP 1781263B1 EP 05746448 A EP05746448 A EP 05746448A EP 05746448 A EP05746448 A EP 05746448A EP 1781263 B1 EP1781263 B1 EP 1781263B1
Authority
EP
European Patent Office
Prior art keywords
weight
pharmaceutical form
inner coating
core
percent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP05746448A
Other languages
German (de)
French (fr)
Other versions
EP1781263A2 (en
Inventor
Hans-Ulrich Petereit
Christian Meier
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Roehm GmbH Darmstadt
Original Assignee
Evonik Roehm GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Evonik Roehm GmbH filed Critical Evonik Roehm GmbH
Priority to SI200530505T priority Critical patent/SI1781263T1/en
Priority to PL05746448T priority patent/PL1781263T3/en
Publication of EP1781263A2 publication Critical patent/EP1781263A2/en
Application granted granted Critical
Publication of EP1781263B1 publication Critical patent/EP1781263B1/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer

Definitions

  • the invention relates to a multilayer dosage form composed of a core with a pharmaceutical active substance, an inner polymer coating and an outer polymer coating.
  • EP 0 704 207 A2 describes thermoplastic plastics for enterosoluble drug casings. These are copolymers of 16 to 40% by weight of acrylic or methacrylic acid, 30 to 80% by weight of methyl acrylate and 0 to 40% by weight of other alkyl esters of acrylic acid and / or methacrylic acid.
  • EP 0 704 208 A2 describes coating and binding agents for enterosoluble drug casings. These are copolymers of 10 to 25% by weight of methacrylic acid, 40 to 70% by weight of methyl acrylate and 20 to 40% by weight of methyl methacrylate.
  • B. of type EUDRAGIT® E, RS or RL are then additionally provided with the above intestinal juice-soluble envelope.
  • EP 0 519 870 A1 describes oral diclofenac preparations.
  • the active ingredient is applied to a core that is coated in two layers.
  • the inner layer may be of a neutral (meth) acrylate copolymer of the type EUDRAGIT ® NE exist and contains in addition to the usual pharmaceutical excipients, such.
  • As release agents 5 to 20 wt .-% of a pore-forming agent, for. B. iron oxide red.
  • the outer layer is enteric-coated and can, for. B. from a (meth) acrylate copolymer of type EUDRAGIT ® L exist.
  • US 5,643,602 describes oral pharmaceutical dosage forms for the treatment of ulcerative colitis or Crohn's disease.
  • the dosage form has a multilayer structure with a neutral core in the interior and subsequently two polymer layers.
  • the active ingredient is dabe in an inner layer in admixture with a neutral polymer, for. B. Ethycellulose or EUDRAGIT ® NE before.
  • the outer layer is enteric-coated and can, for. B. from a (meth) acrylate copolymer of type EUDRAGIT ® L exist.
  • WO 01/68058 describes a multi-layered dosage form substantially composed of a) a core with a pharmaceutically active agent, b) an inner coating of a copolymer or mixture of copolymers consisting of 85 to 98% by weight of radically polymerized C1 to C4 Alkyl esters of acrylic or methacrylic acid and 15 to 2% by weight of (meth) acrylate monomers having a quaternary ammonium group in the alkyl radical and c) an outer coating of a copolymer consisting of 75 to 95% by weight of free radical polymerized C 1 - to C 4 -alkyl esters of acrylic or methacrylic acid and 5 to 25 wt .-% of (meth) acrylate monomers having an anionic group in the alkyl radical.
  • WO 2004/039357 describes a multilayer dosage form composed of a) a neutral core, b) an inner coating of a methacrylate copolymer and c) an outer coating of a copolymer consisting of 40 to 95 wt .-% radically polymerized C 1 - to C 4- alkyl esters of acrylic or methacrylic acid and 5 to 60 wt .-% (meth) acrylate monomers with an anionic group in the alkyl radical.
  • the dosage form is characterized in that the inner coating consists essentially of a methacrylate copolymer which is at least 90 wt .-% of (meth) acrylate monomers with neutral radicals, a minimum film-forming temperature according to DIN 53 787 of at most 30 ° C and contains the active pharmaceutical ingredient in bound form.
  • Dosage forms according to the WO 01/68058 has excellent properties for the release of active ingredients in the colon. In the stomach, almost no active ingredient is released and it is a uniform and long-lasting drug delivery in the intestine, especially just before or reached in the colon.
  • the type of drug delivery is such that the in vitro requirement is met that in the release test according to USP for two hours at pH 1.2 and subsequent rebuffering to pH 7.0, the active ingredient contained in the period up to 2.0 hours after the start of the test to less than 5% and at the time eight hours after the start of the test to 30 to 80% is released.
  • the coatings of the dosage form described do not always have suitable mechanical properties. Especially with very thin film envelopes, z. As with sparingly soluble or high-dose drugs, the need for increased mechanical strength to stabilize the film coatings in pharmaceutical production processes such as pressing, filling in capsules or sachets or mixing with other pellet preparations. The same applies to dosage forms according to the EP 0 519 870 A1 or WO 2004/039357 ,
  • the invention relates to a multilayer drug form containing
  • Carriers for the coatings are tablets, granules, pellets, crystals of regular or irregular shape.
  • the size of granules, pellets or crystals is usually between 0.01 and 2.5 mm, that of tablets between 2.5 and 30.0 mm.
  • the carriers usually contain from 1 to 95% of the active ingredient and, if appropriate or as a rule, further pharmaceutical auxiliaries.
  • the cores may contain other pharmaceutical excipients: binders such as lactose, cellulose and their derivatives, Polyvinylpyrrolidone (PVP), humectants, disintegrants, lubricants, disintegrants, starch and its derivatives, sugar solubilizers or others.
  • binders such as lactose, cellulose and their derivatives, Polyvinylpyrrolidone (PVP), humectants, disintegrants, lubricants, disintegrants, starch and its derivatives, sugar solubilizers or others.
  • the cores a) can be provided in the usual way with a pharmaceutical active substance by adding the appropriate active ingredient, for. B. as active ingredient powder on carrier particles (Nonpareilles) by means of an aqueous binder.
  • the active substance cores (pellets) can be obtained after drying and sieving in the desired size fraction (eg 0.7 to 1 mm). This method is called u.a. as "powder layering".
  • the active ingredient content of the core can be z. B. 5 to 90 wt .-% amount.
  • the inner coating b) consists of 50 to 95, preferably 60 to 90 wt .-% of a (co) polymer containing from 95 to 100, preferably 98 to 100 wt .-% of free-radically polymerized vinylic monomers with neutral Side groups and 0 to 5, preferably 0 to 2 wt .-% vinylic monomers with anionic side groups composed.
  • the predominantly or completely neutral copolymer preferably has the property of swelling above pH 5.0 in water or in the intestinal juice medium and releasing the active ingredient in a controlled or retarded manner.
  • the drug release characteristics are not exactly the same as those in the WO 01/68058 However, the deviations are surprisingly low. The modification in favor of better mechanical properties therefore appears tolerable throughout. By varying the layer thickness of the inner coating, the release profile can be adjusted if necessary.
  • the inner coating may contain a (co) polymer which consists of 95 to 100, preferably 98 to 100 wt .-% radically polymerized C 1 - to C 4 alkyl esters of acrylic or methacrylic acid and optionally 0 to 5, preferably 0 to 2 wt .-% vinylic monomers with anionic side groups, in particular acrylic and / or methacrylic acid, composed.
  • a (co) polymer which consists of 95 to 100, preferably 98 to 100 wt .-% radically polymerized C 1 - to C 4 alkyl esters of acrylic or methacrylic acid and optionally 0 to 5, preferably 0 to 2 wt .-% vinylic monomers with anionic side groups, in particular acrylic and / or methacrylic acid, composed.
  • C 1 - to C 4 -alkyl esters of acrylic or methacrylic acid are in particular methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate and butyl acrylate.
  • a (meth) acrylate monomer having an anionic group in the alkyl radical may e.g. As acrylic acid, but preferably be methacrylic acid.
  • EUDRAGIT ® NE is a copolymer of 30 wt .-% ethyl acrylate and 70 wt .-% methyl methacrylate.
  • the inner coating may contain a (co) polymer which is polyvinyl acetate or a polyvinyl acetate, respectively.
  • a polyvinyl acetate includes derivatives of polyvinyl acetate.
  • the polyvinyl acetate may be present as a dispersion (eg. As the type Kollicoat ® SR 30 D, manufactured by BASF, polyvinyl acetate dispersion stabilized with povidone and sodium lauryl sulphate).
  • the inner coating contains 5 to 50% by weight of pharmaceutically customary auxiliaries which are not pore formers.
  • pore formers as in the EP 0 519 870 A1 can adversely affect the mechanical properties of the double coating film layer when used as described in U.S. Pat EP 0 519 870 A1 , are present in the inner layer.
  • the inner coating layer may contain a small amount of pore-forming agent without unduly compromising the mechanical properties of the double coating.
  • Pore formers should preferably not be used in the inner coating or only in amounts of less than 5, preferably less than 2 or 1 wt .-%. Such small amounts usually cause no more technical effect. Therefore, no pore-forming agents are particularly preferably contained in the inner coating layer.
  • the pharmaceutically customary auxiliaries which may be contained in the inner coating are selected from the substance classes of plasticizers, stabilizers, dyes, antioxidants, wetting agents, pigments, brighteners, release agents, drying agents, pore formers , in particular water-insoluble pore formers such as kaolin, calcium carbonate, calcium hydrogen phosphate, Magnesium oxide, microcrystalline cellulose, titanium dioxide or iron oxide, and in particular water-soluble pore formers such as povidone K30, polyvinyl alcohol, cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC), methylcellulose or sodium carboxymethylcellulose, sucrose, xylitol, sorbitol, mannitol, maltose, xylose, glucose, potassium chloride, sodium chloride , Polysorbate 80, polyethylene glycol or sodium citrate are not or only in amounts of less than 5, preferably less than 2 or 1 wt .-%.
  • an active ingredient bound in the inner coating layer as in US Pat WO 2004/039357 excited, the mechanical properties of the double coating film layer also adversely affected.
  • the active substance contained in the pharmaceutical form is expediently accommodated in the core layer.
  • the inner coating layer while not expedient, may contain a small amount of active ingredient in a small amount, without necessarily overly affecting the mechanical properties of the coating.
  • the active ingredient content in the inner coating should be less than 2, preferably less than 1. Such small amounts usually cause no more technical effect. Therefore, it is particularly preferred that no active ingredient be contained in the inner coating layer.
  • the layer thickness of the inner coating may, for. B. in the range of 10-100, preferably 20 to 40 microns.
  • the outer coating c) contains a copolymer consisting of 75 to 95 wt .-% of radically polymerized C 1 - to C 4 alkyl esters of acrylic or methacrylic acid and 5 to 25 wt .-% of (meth) acrylate monomers with an anionic group in the alkyl radical, wherein 5 to 30, preferably 8 to 20 wt .-% of pharmaceutically customary excipients, in particular plasticizers, are included.
  • Pore formers should preferably not be used in the outer coating or only in amounts of less than 5, preferably less than 2 or 1 wt .-%. Such small amounts usually cause no more technical effect. Therefore, no pore-forming agents are particularly preferably contained in the outer coating layer.
  • C 1 - to C 4 -alkyl esters of acrylic or methacrylic acid are in particular methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate and butyl acrylate.
  • a (meth) acrylate monomer having an anionic group in the alkyl radical may e.g. As acrylic acid, but preferably be methacrylic acid.
  • (meth) acrylate copolymers of 10 to 30 wt .-%, methyl methacrylate, 50 to 70 wt .-% of methyl acrylate and 5 to 15 wt .-% methacrylic acid (type EUDRAGIT ® FS).
  • copolymers are commercially available and can be obtained in a manner known per se by free-radical bulk, solution, bead or emulsion polymerization. They must be brought into the particle size range according to the invention before processing by suitable grinding, drying or spraying processes. This can be done by simply breaking extruded and cooled granule strands or hot stamping.
  • the emulsion polymerization in the aqueous phase is preferred in the presence of water-soluble initiators and (preferably anionic) emulsifiers (see, for example, US Pat. DE-C 2 135 073 ).
  • the emulsion polymer is preferably produced and used in the form of a 10 to 50% by weight, in particular 30 to 40%, aqueous dispersion.
  • a partial neutralization of the methacrylic acid units is dispensable; However, it is possible, for example, to an extent of up to 5 or 10 mol%, if thickening of the coating agent dispersion should be desired.
  • the weight average of the latex particle size is usually 40 to 100 nm, preferably 50 to 70 nm, which ensures a processing-technically favorable viscosity below 1000 mPa ⁇ s.
  • the layer thickness of the outer coating may, for. B. in the range of 20 to 150, preferably 40 to 80 microns.
  • the total weight of the inner coating may preferably be from 2 to 50, particularly preferably from 10 to 40,% by weight, based on the total weight of the core.
  • the total weight of the core is composed of the active ingredient, the excipients optionally used for the formulation, including optionally used neutral cores (non-pareilles), thus corresponds to the dry weight of the formulation.
  • the total weight of the inner coating is composed of the copolymer and the auxiliaries contained, thus corresponds to the dry weight of the formulation used.
  • the total weight of the outer coating is composed of the copolymer and the optional excipients, for. As plasticizer, together, so corresponds to the dry weight of the formulation used.
  • the total weight of the outer coating may preferably be from 5 to 50, more preferably from 10 to 30, weight percent, based on the total weight of the core and the inner coating.
  • scanning electron micrographs of cross sections of isolated double films with the structure according to the invention show homogeneous, uniform layers with good adhesion at the interface.
  • the pellets obtained can be further processed by means of pharmaceutically customary auxiliaries and in a manner known per se into a multiparticulate dosage form, in particular pellet-containing tablets, minitablets, capsules, sachets or dry juices, which are formulated so that the pellets contained are released in the pH range of the stomach become.
  • the dosage form according to the invention for. B. in pellet form, can be advantageously used as part of a multiparticulate dosage form.
  • the improved mechanical properties prove to be particularly advantageous.
  • the advantages are particularly evident in very thin coatings and / or very high drug loading.
  • the dosage form according to the invention proves to be less susceptible to damage to the coating layers. The result is high process reliability and high reproducibility of the properties of units from different production cycles.
  • the drug release characteristic is not exactly the same as it WO 01/68058 is however similar. The deviations are surprisingly low. The drug form is therefore particularly well suited for the release of active ingredients in the colon.
  • the release test z. B. USP (according to USP XXIV, method B, modified test for "enteric coated products") is known in the art.
  • the test conditions are in particular: Paddle method, 100 revolutions per minute, 37 ° C; pH 1.2 with 0.1 N HCl, pH 7.0 by addition of 0.2 M phosphate buffer and adjusting with 2 N NaOH. See also USP 27-NF22 Supplement 1, Method “Delayed Release” Monograph ⁇ 724> Drug Release.
  • the multi-layered dosage form to be used consists essentially of a core with an active ingredient, an inner and an outer coating.
  • pharmaceutically acceptable excipients may be included, but are not critical to the invention.
  • the pharmaceutical agent may be an aminosalicylate, a sulfonamide or a glucocorticoid, in particular 5-aminosalicylic acid, olsalazine, sulfalazine, prednisone or budesonide.
  • the dosage form may contain a pharmaceutical agent which is an enzyme, a peptide hormone, an immunomodulatory protein, an antigen or antibody.
  • the pharmaceutical form may contain as pharmaceutical active substance a pancreatin, an insulin, a human growth hormone (hGH), corbaplatin, intron A, calcitonin, cromaline, an interferon, a calcitonin, granulocyte colony stimulating factor (G-CSF), an interleukin, parathyroid hormones, Glucagon, pro-somatostatin, a somatostatin, detirelix, cetrorelix, vasopressin, 1-deaminocysteine-8-D-arginine vasopressin, leuprolide acetate or an antigen derived from grasses or other plants such as e.g. As rye, wheat, barley, oats, bermuda grass, horsetail, maple, elm, oak, sycamore, poplar, cedar, horsetail, thistles was obtained.
  • a pancreatin an insulin
  • hGH human growth hormone
  • corbaplatin corba
  • pore formers are excluded in amounts from 5% by weight, based on the inner coating.
  • Dry-action agents have the following properties: they have large specific surfaces, are chemically inert, have good free-flowing properties and are finely divided. Based on these Properties reduce the tackiness of polymers containing as functional groups polar comonomers.
  • dryers are:
  • z. B stabilizers, dyes, antioxidants, wetting agents, pigments, brighteners, etc. They serve primarily as a processing aid and should be able to ensure a safe and reproducible production process and good long-term storage stability.
  • Other pharmaceutically customary auxiliaries can be present in amounts of from 0.001% by weight to 30% by weight, preferably from 0.1 to 10% by weight, based on the copolymer.
  • Plasticizers Substances suitable as plasticizers generally have a molecular weight between 100 and 20,000 and contain one or more hydrophilic groups in the molecule, eg. B. hydroxyl, ester or amino groups. Suitable are citrates, phthalates, sebacates, castor oil. Examples of suitable Plasticizers are citric acid alkyl esters, glycerol esters, alkyl phthalates, sebacic acid alkyl esters, sucrose esters, sorbitan esters, dibutyl sebacate and polyethylene glycols 4000 to 20,000.
  • Preferred plasticizers are tributyl citrate, triethyl citrate, acetyl triethyl citrate, dibutyl sebacate and diethyl sebacate.
  • the amounts used are between 1 and 35, preferably 2 to 10 wt .-%, based on the respective polymer or copolymer.
  • the dosage form described may be in the form of a coated tablet, in the form of a compressed pellet pellet or in the form of pellets which are placed in a capsule, e.g. As gelatin, starch or cellulose derivatives are filled.
  • EUDRAGIT ® RS copolymer of 65 wt .-% methyl methacrylate, 30 wt .-% ethyl acrylate and 5 wt .-% of 2-trimethylammoniumethyl methacrylate chloride.
  • EUDRAGIT ® RL copolymer of 6 wt .-% methyl methacrylate, 30 wt .-% ethyl acrylate and 10 wt .-% of 2-trimethylammoniumethyl methacrylate chloride.
  • EUDRAGIT ® NE copolymer of 30 wt .-% ethyl acrylate and 70 wt .-% methyl methacrylate.
  • EUDRAGIT ® FS 30 D formulation 10% aqueous
  • the dispersion is diluted to 10%: In a 400 ml beaker TEC and water were weighed and stirred at 400 rpm on the magnetic stirrer until the dissolution of the TEC until a clear solution.
  • TEC triethyl citrate
  • EUDRAGIT ® RS 30 D / RL 30 D (1: 1) formulation, 10% aqueous
  • each EUDRAGIT ® RS 30 D / RL 30D 1: 1 dispersion and 20% (based on polymer) triethylcitrate, with deionized water, the dispersion is diluted to 10%:
  • EUDRAGIT ® NE 30D formulation 10% aqueous
  • the clear solution then becomes air bubble leakage Allowed to stand for 5 min at room temperature.
  • the amount of polyvinyl acetate dispersion filtered through an approximately 0.1 to 0.2 mm metal sieve is placed in a 500 ml PE screw-type bottle and the aq. Stirred at about 400 ⁇ 100 rpm while stirring with the magnetic stirrer. Propylene glycol - Kollidon ® 25 solution added.
  • the formulation is stirred at room temperature overnight at this speed.
  • the approximately 256 cm 2 spout inside surface of the glass plate is then brushed with a pressure-sensitive adhesive once and dried with a hot air dryer.
  • the spouted glass plates prepared in this way are now balanced in a circulating air drying cabinet with a spirit level.
  • each 64 g of a filtered through a metal is now 10% EUDRAGIT ® - or poured other sample.
  • 2- layered film having polyvinyl acetate shows a slightly yellowish milky turbidity (5 days drying) and ethyl cellulose (Aquacoat ® ECD 30) has a slightly cracked turbidity problems of adhesion to the lower film (3 days drying).
  • the 2-ply films now obtained are cooled to room temperature, carefully detached from the aluminum foil, and each stored individually in filter paper bags, which in turn are sealed in a PE bag.
  • 2nd layer EUDRAGIT ® FS 9 inventively 1st layer EUDRAGIT ® NE 7.0 174 2nd layer EUDRAGIT ® FS 10 inventively 1st layer of polyvinyl acetate 8.0 288 2nd layer EUDRAGIT ® FS

Abstract

The invention relates to a medicament in a multilayer form, containing a) a core with a pharmaceutical agent, b) an inner coating, 50 to 95 percent by weight of which arc composed of a (co)polymer comprising 95 to 100 percent by weight of radically polymerized vinylic monomers with neutral side groups and 0 to 5 percent by weight of monomers with anionic side groups, c) an outer coaling made of a copolymer comprising 75 to 95 percent by weight of radically polymerized C1 to C4 alkyl esters of acrylic acid or methacrylic acid and 5 to 25 percent by weight of (meth)acrylate monomers with an anionic group in the alkyl radical. Said medicament further contains 5 to 30 percent by weight of common pharmaceutical auxiliaries, particularly emollients. The inventive medicament is characterized in that the inner coaling contains 5 to 50 percent by weight of common pharmaceutical auxiliaries which are no expanding agents while the amount of expanding agents provided is less than 5 percent by weight.

Description

Die Erfindung betrifft eine mehrschichtige Arzneiform, aufgebaut aus einem Kern mit einem pharmazeutischen Wirkstoff, einem inneren Polymerüberzug und einem äußeren Polymerüberzug.The invention relates to a multilayer dosage form composed of a core with a pharmaceutical active substance, an inner polymer coating and an outer polymer coating.

Stand der TechnikState of the art

EP 0 704 207 A2 beschreibt thermoplastische Kunststoffe für darmsaftlösliche Arzneiumhüllungen. Es handelt sich dabei um Mischpolymerisate aus 16 bis 40 Gew.-% Acryl- oder Methacrylsäure, 30 bis 80 Gew.-% Methylacrylat und 0 bis 40 Gew.-% anderen Alkylestern der Acrylsäure und/oder Methacrylsäure. EP 0 704 207 A2 describes thermoplastic plastics for enterosoluble drug casings. These are copolymers of 16 to 40% by weight of acrylic or methacrylic acid, 30 to 80% by weight of methyl acrylate and 0 to 40% by weight of other alkyl esters of acrylic acid and / or methacrylic acid.

EP 0 704 208 A2 beschreibt Überzugs- und Bindemittel für darmsaftlösliche Arzneiumhüllungen. Es handelt sich dabei um Copolymerisate aus 10 bis 25 Gew.-% Methacrylsäure, 40 bis 70 Gew.-% Methylacrylat und 20 bis 40 Gew-% Methylmethacrylat. Die Beschreibung erwähnt neben einschichtigen Überzügen auch mehrlagige Überzugssysteme. Diese können aus einem Kern, der z. B. einen basischen oder einen wasserempfindlichen Wirkstoff enthält, bestehen, weisen eine Isolierschicht aus einem anderen Überzugsmaterial, wie Celluloseether, Celluloseester oder einem kationischen Polymethacrylat z. B. von Typ EUDRAGIT® E, RS oder RL auf und werden dann zusätzlich mit der oben genannten darmsaftlöslichen Umhüllung versehen. EP 0 704 208 A2 describes coating and binding agents for enterosoluble drug casings. These are copolymers of 10 to 25% by weight of methacrylic acid, 40 to 70% by weight of methyl acrylate and 20 to 40% by weight of methyl methacrylate. The description mentions in addition to single-layer coatings also multi-layer coating systems. These can consist of a core, the z. B. contains a basic or a water-sensitive active ingredient consist, have an insulating layer of another coating material such as cellulose ether, cellulose ester or a cationic polymethacrylate z. B. of type EUDRAGIT® E, RS or RL and are then additionally provided with the above intestinal juice-soluble envelope.

EP 0 519 870 A1 beschreibt orale Diclofenac-Zubereitungen. Der Wirkstoff ist dabei auf einem Kern aufgetragen, der zweischichtig überzogen ist. Die innere Schicht kann aus einem neutralen (Meth)acrylatcopolymeren von Typ EUDRAGIT® NE bestehen und enthält neben den pharmazeutisch üblichen Hilfsstoffen, wie z. B. Trennmitteln, 5 bis 20 Gew.-% eines Porenbildners, z. B. Eisenoxid rot. Die äußere Schicht ist magensaftresistent und kann z. B. aus einem (Meth)acrylatcopolymer von Typ EUDRAGIT® L bestehen. EP 0 519 870 A1 describes oral diclofenac preparations. The active ingredient is applied to a core that is coated in two layers. The inner layer may be of a neutral (meth) acrylate copolymer of the type EUDRAGIT ® NE exist and contains in addition to the usual pharmaceutical excipients, such. As release agents, 5 to 20 wt .-% of a pore-forming agent, for. B. iron oxide red. The outer layer is enteric-coated and can, for. B. from a (meth) acrylate copolymer of type EUDRAGIT ® L exist.

US 5,643,602 beschreibt orale pharmazeutische Arzneiformen zur Therapie der Colitis ulcerosa oder Morbus Crohn. Die Arzneiform hat einen mehrschichtigen Aufbau mit einem neutraler Kern in Inneren und darauf folgend zwei Polymerschichten. Der Wirkstoff liegt dabe in einer inneren Schicht in Mischung mit einem neutralen Polymeren, z. B. Ethycellulose oder EUDRAGIT® NE vor. Die äußere Schicht ist magensaftresistent und kann z. B. aus einem (Meth)acrylatcopolymer von Typ EUDRAGIT® L bestehen. US 5,643,602 describes oral pharmaceutical dosage forms for the treatment of ulcerative colitis or Crohn's disease. The dosage form has a multilayer structure with a neutral core in the interior and subsequently two polymer layers. The active ingredient is dabe in an inner layer in admixture with a neutral polymer, for. B. Ethycellulose or EUDRAGIT ® NE before. The outer layer is enteric-coated and can, for. B. from a (meth) acrylate copolymer of type EUDRAGIT ® L exist.

WO 01/68058 beschreibt eine mehrschichtige Arzneiform, die im wesentlichen aufgebaut ist aus a) einem Kern mit einem pharmazeutischen Wirkstoff, b) einem inneren Überzug aus einem Copolymeren oder einer Mischung von Copolymeren, die sich aus 85 bis 98 Gew.-% radikalisch polymerisierten C1-bis C4-Alkylestern der Acryl- oder der Methacrylsäure und 15 bis 2 Gew.-% (Meth)acrylat-Monomeren mit einer quaternären Ammoniumgruppe im Alkylrest zusammensetzen und c) einem äußeren Überzug aus einem Copolymeren, das sich aus 75 bis 95 Gew.-% radikalisch polymerisierten C1- bis C4-Alkylestern der Acryl- oder der Methacrylsäure und 5 bis 25 Gew.-% (Meth)acrylatMonomeren mit einer anionischen Gruppe im Alkylrest zusammensetzt. WO 01/68058 describes a multi-layered dosage form substantially composed of a) a core with a pharmaceutically active agent, b) an inner coating of a copolymer or mixture of copolymers consisting of 85 to 98% by weight of radically polymerized C1 to C4 Alkyl esters of acrylic or methacrylic acid and 15 to 2% by weight of (meth) acrylate monomers having a quaternary ammonium group in the alkyl radical and c) an outer coating of a copolymer consisting of 75 to 95% by weight of free radical polymerized C 1 - to C 4 -alkyl esters of acrylic or methacrylic acid and 5 to 25 wt .-% of (meth) acrylate monomers having an anionic group in the alkyl radical.

WO 2004/039357 beschreibt eine mehrschichtige Arzneiform, aufgebaut aus a) einem neutralen Kern, b) einem inneren Überzug aus einem Methacrylat-Copolymeren und c) einem äußeren Überzug aus einem Copolymeren, das sich aus 40 bis 95 Gew.-% radikalisch polymerisierten C1- bis C4-Alkylestern der Acryl- oder der Methacrylsäure und 5 bis 60 Gew.-% (Meth)acrylatMonomeren mit einer anionischen Gruppe im Alkylrest zusammensetzt. Die Arzneiform ist dadurch gekennzeichnet, daß der innere Überzug im wesentlichen aus einem Methacrylat-Copolymeren besteht, das mindestens zu 90 Gew.-% aus (Meth)acrylat-Monomeren mit neutralen Resten aufgebaut ist, eine Mindestfilmbildetemperatur nach DIN 53 787 von höchstens 30°C aufweist und den pharmazeutischen Wirkstoff in gebundener Form enthält. WO 2004/039357 describes a multilayer dosage form composed of a) a neutral core, b) an inner coating of a methacrylate copolymer and c) an outer coating of a copolymer consisting of 40 to 95 wt .-% radically polymerized C 1 - to C 4- alkyl esters of acrylic or methacrylic acid and 5 to 60 wt .-% (meth) acrylate monomers with an anionic group in the alkyl radical. The dosage form is characterized in that the inner coating consists essentially of a methacrylate copolymer which is at least 90 wt .-% of (meth) acrylate monomers with neutral radicals, a minimum film-forming temperature according to DIN 53 787 of at most 30 ° C and contains the active pharmaceutical ingredient in bound form.

Aufgabe und LösungTask and solution

Arzneiformen gemäß der WO 01/68058 weist hervorragende Eigenschaften für Freisetzung von Wirkstoffen im Colon auf. Im Magen wird nahezu kein Wirkstoff abgegeben und es wird eine gleichmäßige und langanhaltende Wirkstoffabgabe im Darm, insbesondere kurz vor oder erst im Dickdarmbereich erreicht. Die Art der Wirkstoffabgabe ist dergestalt, daß die in-vitro Anforderung erfüllt wird, daß im Freisetzungstest nach USP zwei Stunden bei pH 1,2 und anschließendem Umpuffern auf pH 7,0 der enthaltene Wirkstoff im Zeitraum bis 2,0 Stunden nach Testbeginn zu weniger als 5 % und zum Zeitpunkt acht Stunden nach Testbeginn zu 30 bis 80 % freigesetzt wird.Dosage forms according to the WO 01/68058 has excellent properties for the release of active ingredients in the colon. In the stomach, almost no active ingredient is released and it is a uniform and long-lasting drug delivery in the intestine, especially just before or reached in the colon. The type of drug delivery is such that the in vitro requirement is met that in the release test according to USP for two hours at pH 1.2 and subsequent rebuffering to pH 7.0, the active ingredient contained in the period up to 2.0 hours after the start of the test to less than 5% and at the time eight hours after the start of the test to 30 to 80% is released.

Es wurde jedoch festgestellt, dass die Überzüge der beschriebenen Arzneiform nicht immer geeignete mechanische Eigenschaften aufweist. Insbesondere bei sehr dünnen Filmhüllen, z. B. bei schwerlöslichen oder hochdosierten Arzneistoffen besteht der Bedarf erhöhter mechanischer Festigkeit zur Stabilisierung der Filmüberzüge bei pharmaüblichen Produktionsvorgängen wie Verpressen, Abfüllen in Kapseln bzw. Sachets oder Mischen mit anderen Pelletpräparationen. Ähnliches gilt für Arzneiformen gemäß der EP 0 519 870 A1 oder WO 2004/039357 .However, it has been found that the coatings of the dosage form described do not always have suitable mechanical properties. Especially with very thin film envelopes, z. As with sparingly soluble or high-dose drugs, the need for increased mechanical strength to stabilize the film coatings in pharmaceutical production processes such as pressing, filling in capsules or sachets or mixing with other pellet preparations. The same applies to dosage forms according to the EP 0 519 870 A1 or WO 2004/039357 ,

Es wurde somit als eine Aufgabe gesehen, eine Arzneiform mit zumindest sehr ähnlicher Freisetzungscharakteristik bereitzustellen, die jedoch in den mechanischen Eigenschaften des Filmüberzugs verbessert ist.It has thus been considered an object to provide a dosage form having at least very similar release characteristics, but which is improved in the mechanical properties of the film coating.

Die Aufgabe wird gelöst durch eine mehrschichtige Arzneiform, enthaltend

  1. a) einen Kern mit einem pharmazeutischen Wirkstoff
  2. b) einen inneren Überzug, der zu 50 bis 95 Gew.-% aus einem (Co)polymeren besteht, das sich zu 95 bis 100 Gew.-% aus radikalisch polymerisierten vinylischen Monomeren mit neutralen Seitengruppen und 0 bis 5 Gew.-% Monomeren mit anionischen Seitengruppen zusammensetzt,
  3. c) einen äußeren Überzug aus einem Copolymeren, das sich aus 75 bis 95 Gew.-% radikalisch polymerisierten C1- bis C4-Alkylestern der Acryl- oder der Methacrylsäure und 5 bis 25 Gew.-% (Meth)acrylat-Monomeren mit einer anionischen Gruppe im Alkylrest zusammensetzt, wobei 5 bis 30 Gew.-% an pharmazeutisch üblichen Hilfsstoffen, insbesondere Weichmacher, enthalten sind,
dadurch gekennzeichnet, daß
der innere Überzug 5 bis 50 Gew.-% an pharmazeutisch üblichen Hilfsstoffen enthält, die keine Porenbildner sind und Porenbildner nur in Mengen von weniger als 5 Gew.-% enthalten sind.The object is achieved by a multi-layer drug form containing
  1. a) a core with a pharmaceutical agent
  2. b) an inner coating consisting of from 50 to 95% by weight of a (co) polymer comprising from 95 to 100% by weight of free-radically polymerized vinylic monomers having pendant neutral groups and from 0 to 5% by weight of monomers composed of anionic side groups,
  3. c) an outer coating of a copolymer consisting of 75 to 95 wt .-% radically polymerized C 1 - to C 4 alkyl esters of acrylic or methacrylic acid and 5 to 25 wt .-% (meth) acrylate monomers with an anionic group in the alkyl radical, wherein 5 to 30 wt .-% of pharmaceutically customary excipients, in particular plasticizers, are included,
characterized in that
the inner coating contains 5 to 50% by weight of pharmaceutically customary auxiliaries which are not pore-forming agents and contain pore-forming agents only in amounts of less than 5% by weight.

Die Kombination des inneren und der äußeren Überzugsfilms führen offenbar in zu einer gesteigerten Zugfestigkeit der doppelten Filmschicht als Ganzes im Vergleich zu WO 01/68058 . Dadurch werden die mechanischen Eigenschaften der Arzneiform selbst und daraus hergestellter mulipartikulärer Arzneiformen deutlich verbessert. Man kann die Eigenschaftsverbesserung an isolierten doppelten Filmschichten erkennen. Bei erfindungsgemäß aufgebauten, isolierten Doppelfilmschichten werden Zugfestigkeiten im Bereich von 6 bis 10 [Mpa] und nominale Bruchdehnungen im Bereich von 170 bis 300 [%] gemessen.The combination of the inner and outer coating films appears to result in increased tensile strength of the double film layer as a whole compared to WO 01/68058 , This will change the mechanical properties the drug form itself and derived therefrom Mulipartikulärer drug forms significantly improved. One can see the property improvement on isolated double film layers. In isolated double-layer films constructed according to the invention, tensile strengths in the range of 6 to 10 [Mpa] and nominal elongations at break in the range of 170 to 300 [%] are measured.

Ausführung der ErfindungEmbodiment of the invention Die Erfindung betrifft eine mehrschichtige Arzneiform, enthaltendThe invention relates to a multilayer drug form containing Kern a)Core a)

Träger bzw. Kerne für die Überzüge sind Tabletten, Granulate, Pellets, Kristalle von regelmäßiger oder unregelmäßiger Form. Die Größe von Granulaten, Pellets oder Kristallen liegt in der Regel zwischen 0,01 und 2,5 mm, die von Tabletten zwischen 2,5 und 30,0 mm. Die Träger enthalten üblicherweise zu 1 bis 95 % Wirkstoff sowie gegebenenfalls bzw. in der Regel weitere pharmazeutische Hilfsstoffe.Carriers for the coatings are tablets, granules, pellets, crystals of regular or irregular shape. The size of granules, pellets or crystals is usually between 0.01 and 2.5 mm, that of tablets between 2.5 and 30.0 mm. The carriers usually contain from 1 to 95% of the active ingredient and, if appropriate or as a rule, further pharmaceutical auxiliaries.

Übliche Herstellungsverfahren sind direktes Verpressen, Verpressen von Trocken-, Feucht- oder Sintergranulaten, Extrusion und anschließende Ausrundung, feuchte oder trockene Granulation oder direkte Pelletierung (z.B. auf Tellern) oder durch Binden von Pulvern (Powder layering) auf wirkstofffreie Kugeln (Nonpareilles) oder wirkstoffhaltige Partikeln.Conventional production methods are direct compression, pressing of dry, moist or sintered granules, extrusion and subsequent rounding, wet or dry granulation or direct pelleting (eg on plates) or by binding of powders (powder layering) on active-ingredient-free balls (nonpareils) or active ingredient-containing particles.

Neben dem Wirkstoff können die Kerne weitere pharmazeutische Hilfsstoffe enthalten: Bindemittel, wie Lactose, Cellulose und deren Derivate, Polyvinylpyrrolidon (PVP), Feuchthaltemittel, Zerfallsförderer, Gleitmittel, Sprengmittel, Stärke und deren Derivate, Zucker Solubilisatoren oder andere.In addition to the active ingredient, the cores may contain other pharmaceutical excipients: binders such as lactose, cellulose and their derivatives, Polyvinylpyrrolidone (PVP), humectants, disintegrants, lubricants, disintegrants, starch and its derivatives, sugar solubilizers or others.

Die Kerne a) können in üblicher Weise mit einem pharmazeutischen Wirkstoff versehen werden, indem man den entsprechenden Wirkstoff, z. B. als Wirkstoffpulver auf Trägerpartikel (Nonpareilles) mittels eines wäßrigen Bindemittels aufbringt. Die Wirkstoffkerne (Pellets) können nach Trocknung und Siebung in der gewünschten Größenfraktion erhalten werden (z. B. 0,7 bis 1 mm). Man bezeichnet dieses Verfahren u.a. als "Powder Layering". Der Wirkstoffgehalt des Kerns kann z. B. 5 bis 90 Gew.-% betragen.The cores a) can be provided in the usual way with a pharmaceutical active substance by adding the appropriate active ingredient, for. B. as active ingredient powder on carrier particles (Nonpareilles) by means of an aqueous binder. The active substance cores (pellets) can be obtained after drying and sieving in the desired size fraction (eg 0.7 to 1 mm). This method is called u.a. as "powder layering". The active ingredient content of the core can be z. B. 5 to 90 wt .-% amount.

Innerer Überzug b)Inner cover b)

Der innere Überzug b) besteht zu 50 bis 95, bevorzugt zu 60 bis 90 Gew.-% aus einem (Co)polymeren, das sich zu 95 bis 100, bevorzugt zu 98 bis 100 Gew.-% aus radikalisch polymerisierten vinylischen Monomeren mit neutralen Seitengruppen und 0 bis 5, bevorzugt 0 bis 2 Gew.-% vinylischen Monomeren mit anionischen Seitengruppen zusammensetzt. Das überwiegend oder völlig neutrale Copolymer hat bevorzugt die Eigenschaft, oberhalb von pH 5,0 in Wasser bzw. im Darmsaftmillieu zu quellen und den Wirkstoff kontrolliert bzw. retardiert freizusetzen.The inner coating b) consists of 50 to 95, preferably 60 to 90 wt .-% of a (co) polymer containing from 95 to 100, preferably 98 to 100 wt .-% of free-radically polymerized vinylic monomers with neutral Side groups and 0 to 5, preferably 0 to 2 wt .-% vinylic monomers with anionic side groups composed. The predominantly or completely neutral copolymer preferably has the property of swelling above pH 5.0 in water or in the intestinal juice medium and releasing the active ingredient in a controlled or retarded manner.

Die Wirkstofffreisetzungscharakteristik entspricht nicht exakt derjenigen, wie sie in der WO 01/68058 beschrieben ist, die Abweichungen sind jedoch überraschend gering. Die Modifikation zugunsten der besseren mechanischen Eigenschaften erscheint deshalb durchgängig tolerierbar. Durch Variation der Schichtdicke des inneren Überzuges kann das Freigabeprofil gegebenenfalls angeglichen werden.The drug release characteristics are not exactly the same as those in the WO 01/68058 However, the deviations are surprisingly low. The modification in favor of better mechanical properties therefore appears tolerable throughout. By varying the layer thickness of the inner coating, the release profile can be adjusted if necessary.

Der innere Überzug kann ein (Co)polymer enthalten, das sich aus 95 bis 100, bevorzugt 98 bis 100 Gew.-% radikalisch polymerisierten C1- bis C4-Alkylestern der Acryl- oder der Methacrylsäure und gegebenenfalls 0 bis 5, bevorzugt 0 bis 2 Gew.-% vinylischen Monomeren mit anionischen Seitengruppen, insbesondere Acryl- und/oder Methacrylsäure, zusammensetzt.The inner coating may contain a (co) polymer which consists of 95 to 100, preferably 98 to 100 wt .-% radically polymerized C 1 - to C 4 alkyl esters of acrylic or methacrylic acid and optionally 0 to 5, preferably 0 to 2 wt .-% vinylic monomers with anionic side groups, in particular acrylic and / or methacrylic acid, composed.

C1- bis C4-Alkylestern der Acryl- oder Methacrylsäure sind insbesondere Methylmethacrylat, Ethylmethacrylat, Butylmethacrylat, Methylacrylat, Ethylacrylat und Butylacrylat.C 1 - to C 4 -alkyl esters of acrylic or methacrylic acid are in particular methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate and butyl acrylate.

Ein (Meth)acrylat-Monomer mit einer anionischen Gruppe im Alkylrest kann z. B. Acrylsäure, bevorzugt jedoch Methacrylsäure sein.A (meth) acrylate monomer having an anionic group in the alkyl radical may e.g. As acrylic acid, but preferably be methacrylic acid.

Geeignet sind z. B. neutrale (Meth)acrylat Copolymere aus 20 bis 40 Gew.-% Ethylacrylat und 60 bis 80 Gew.-% Methylmethacrylat (Typ EUDRAGIT® NE).Suitable z. B. neutral (meth) acrylate copolymers of 20 to 40 wt .-% ethyl acrylate and 60 to 80 wt .-% methyl methacrylate (type EUDRAGIT ® NE).

EUDRAGIT® NE ist ein Copolymer aus 30 Gew.-% Ethylacrylat und 70 Gew.-% Methylmethacrylat.EUDRAGIT ® NE is a copolymer of 30 wt .-% ethyl acrylate and 70 wt .-% methyl methacrylate.

Der innere Überzug kann ein (Co)polymer enthalten, das Polyvinylacetat bzw. ein Polyvinylacetat ist. Der Begriff "ein Polyvinylacetat" schließt Derivate des Polyvinylacetats mit ein. Das Polyvinylacetat kann als Dispersion vorliegen (z. B. vom Typ Kollicoat® SR 30 D, Hersteller BASF, Polyvinylacetat Dispersion, stabilisiert mit Povidon und Na-Laurylsulfat).The inner coating may contain a (co) polymer which is polyvinyl acetate or a polyvinyl acetate, respectively. The term "a polyvinyl acetate" includes derivatives of polyvinyl acetate. The polyvinyl acetate may be present as a dispersion (eg. As the type Kollicoat ® SR 30 D, manufactured by BASF, polyvinyl acetate dispersion stabilized with povidone and sodium lauryl sulphate).

Der innere Überzug enthält 5 bis 50 Gew.-% an pharmazeutisch üblichen Hilfsstoffen, die keine Porenbildner sind.The inner coating contains 5 to 50% by weight of pharmaceutically customary auxiliaries which are not pore formers.

Es wurde festgestellt, daß Porenbildner, wie sie in der EP 0 519 870 A1 verwendet werden, die mechanischen Eigenschaften der doppelten Überzugsfilmschicht nachteilig beeinflussen, wenn diese, wie in der EP 0 519 870 A1 , in der inneren Schicht vorhanden sind. Die innere Überzugsschicht kann, auch wenn dies nicht zweckmäßig erscheint, in geringer Menge Porenbildner enthalten, ohne, dass die mechanischen Eigenschaften des doppelten Überzugs zwangsläufig zu sehr beeinträchtigt werden. Porenbildner sollten im inneren Überzug bevorzugt nicht oder nur in Mengen von weniger als 5, bevorzugt weniger als 2 oder 1 Gew.-% verwendet werden. Derartig geringe Mengen bewirken in der Regel keinen technischen Effekt mehr. Besonders bevorzugt sind deshalb keine Porenbildner in der inneren Überzugsschicht enthalten.It was found that pore formers, as in the EP 0 519 870 A1 can adversely affect the mechanical properties of the double coating film layer when used as described in U.S. Pat EP 0 519 870 A1 , are present in the inner layer. The inner coating layer, while not expedient, may contain a small amount of pore-forming agent without unduly compromising the mechanical properties of the double coating. Pore formers should preferably not be used in the inner coating or only in amounts of less than 5, preferably less than 2 or 1 wt .-%. Such small amounts usually cause no more technical effect. Therefore, no pore-forming agents are particularly preferably contained in the inner coating layer.

Die pharmazeutisch üblichen Hilfsstoffe, die im inneren Überzug enthalten sein können, werden aus den Stoffklassen der Weichmacher, Stabilisatoren, Farbstoffe, Antioxidantien, Netzmittel, Pigmente, Glanzmittel, Trennmittel, Trockenstellmittel ausgewählt, wobei Porenbildner, insbesondere wasserunlösliche Porenbildner wie Kaolin, Calciumcarbonat, Calciumhydrogenphosphat, Magnesiumoxid, mikrokristalline Cellulose, Titandioxid oder Eisenoxid, und insbesondere wasserlösliche Porenbildner wie Povidone K30, Polyvinylalkohol, Cellulosederivate, wie Hydroxypropylcellulose, Hydroxypropylmethylcellulose (HPMC), Methylcellulose oder Natriumcarboxymethylcellulose, Saccharose, Xylit, Sorbit, Mannit, Maltose, Xylose, Glucose, Kaliumchlorid, Natriumchlorid, Polysorbat 80, Poylethylenglykol oder Natriumcitrat nicht oder nur in Mengen von weniger als 5, bevorzugt weniger als 2 oder 1 Gew.-% enthalten sind.The pharmaceutically customary auxiliaries which may be contained in the inner coating are selected from the substance classes of plasticizers, stabilizers, dyes, antioxidants, wetting agents, pigments, brighteners, release agents, drying agents, pore formers , in particular water-insoluble pore formers such as kaolin, calcium carbonate, calcium hydrogen phosphate, Magnesium oxide, microcrystalline cellulose, titanium dioxide or iron oxide, and in particular water-soluble pore formers such as povidone K30, polyvinyl alcohol, cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC), methylcellulose or sodium carboxymethylcellulose, sucrose, xylitol, sorbitol, mannitol, maltose, xylose, glucose, potassium chloride, sodium chloride , Polysorbate 80, polyethylene glycol or sodium citrate are not or only in amounts of less than 5, preferably less than 2 or 1 wt .-%.

Es wurde weiterhin festgestellt, daß ein in der inneren Überzugsschicht gebundener Wirkstoff, wie in der WO 2004/039357 angeregt, die mechanischen Eigenschaften der doppelten Überzugsfilmschicht ebenfalls nachteilig beeinflusst. Der in der Arzneiform enthaltene Wirkstoff wird zweckmäßigerweise in der Kernschicht untergebracht. Die innere Überzugsschicht kann, auch wenn dies nicht zweckmäßig erscheint, in geringer Menge etwas Wirkstoff enthalten, ohne, daß die mechanischen Eigenschaften des Überzugs zwangsläufig zu sehr beeinträchtigt werden. Der Wirkstoffgehalt sollte im inneren Überzug jedoch bei weniger als 2, bevorzugt weniger als 1 liegen. Derartig geringe Mengen bewirken in der Regel keinen technischen Effekt mehr. Besonders bevorzugt ist deshalb kein Wirkstoff in der inneren Überzugsschicht enthalten.It has further been found that an active ingredient bound in the inner coating layer, as in US Pat WO 2004/039357 excited, the mechanical properties of the double coating film layer also adversely affected. The active substance contained in the pharmaceutical form is expediently accommodated in the core layer. The inner coating layer, while not expedient, may contain a small amount of active ingredient in a small amount, without necessarily overly affecting the mechanical properties of the coating. However, the active ingredient content in the inner coating should be less than 2, preferably less than 1. Such small amounts usually cause no more technical effect. Therefore, it is particularly preferred that no active ingredient be contained in the inner coating layer.

Die Schichtdicke des inneren Überzugs kann z. B. im Bereich von 10-100, bevorzugt 20 bis 40 µm liegen.The layer thickness of the inner coating may, for. B. in the range of 10-100, preferably 20 to 40 microns.

Äußerer Überzug c)Outer cover c)

Der äußere Überzug c) enthält ein Copolymer, das sich aus 75 bis 95 Gew.-% radikalisch polymerisierten C1- bis C4-Alkylestern der Acryl- oder der Methacrylsäure und 5 bis 25 Gew.-% (Meth)acrylat-Monomeren mit einer anionischen Gruppe im Alkylrest zusammensetzt, wobei 5 bis 30, bevorzugt 8 bis 20 Gew.-% an pharmazeutisch üblichen Hilfsstoffen, insbesondere Weichmacher, enthalten sind. Porenbildner sollen im äußeren Überzug bevorzugt nicht oder nur in Mengen von weniger als 5, bevorzugt weniger als 2 oder 1 Gew.-% verwendet werden. Derartig geringe Mengen bewirken in der Regel keinen technischen Effekt mehr. Besonders bevorzugt sind deshalb keine Porenbildner in der äußeren Überzugsschicht enthalten.The outer coating c) contains a copolymer consisting of 75 to 95 wt .-% of radically polymerized C 1 - to C 4 alkyl esters of acrylic or methacrylic acid and 5 to 25 wt .-% of (meth) acrylate monomers with an anionic group in the alkyl radical, wherein 5 to 30, preferably 8 to 20 wt .-% of pharmaceutically customary excipients, in particular plasticizers, are included. Pore formers should preferably not be used in the outer coating or only in amounts of less than 5, preferably less than 2 or 1 wt .-%. Such small amounts usually cause no more technical effect. Therefore, no pore-forming agents are particularly preferably contained in the outer coating layer.

C1- bis C4-Alkylestern der Acryl- oder Methacrylsäure sind insbesondere Methylmethacrylat, Ethylmethacrylat, Butylmethacrylat, Methylacrylat, Ethylacrylat und Butylacrylat.C 1 - to C 4 -alkyl esters of acrylic or methacrylic acid are in particular methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate and butyl acrylate.

Ein (Meth)acrylat-Monomer mit einer anionischen Gruppe im Alkylrest kann z. B. Acrylsäure, bevorzugt jedoch Methacrylsäure sein.A (meth) acrylate monomer having an anionic group in the alkyl radical may e.g. As acrylic acid, but preferably be methacrylic acid.

Besonders gut geeignet sind (Meth)acrylat Copolymere aus 10 bis 30 Gew.-%, Methylmethacrylat, 50 bis 70 Gew.-% Methylacrylat und 5 bis 15 Gew.-% Methacrylsäure (Typ EUDRAGIT® FS).Particularly suitable are (meth) acrylate copolymers of 10 to 30 wt .-%, methyl methacrylate, 50 to 70 wt .-% of methyl acrylate and 5 to 15 wt .-% methacrylic acid (type EUDRAGIT ® FS).

Die Copolymere sind handelsüblich und können in an sich bekannter Weise durch radikalische Substanz-, Lösungs-, Perl- oder Emulsionspolymerisation erhalten werden. Sie müssen vor der Verarbeitung durch geeignete Mahl-, Trocken- oder Sprühprozesse in den erfindungsgemäßen Teilchengrößenbereich gebracht werden. Dies kann durch einfaches Brechen extrudierter und abgekühlter Granulatstränge oder Heißabschlag erfolgen.The copolymers are commercially available and can be obtained in a manner known per se by free-radical bulk, solution, bead or emulsion polymerization. They must be brought into the particle size range according to the invention before processing by suitable grinding, drying or spraying processes. This can be done by simply breaking extruded and cooled granule strands or hot stamping.

Bevorzugt ist die Emulsionspolymerisation in wäßriger Phase in Gegenwart wasserlöslicher Initiatoren und (vorzugsweise anionischer) Emulgatoren (Siehe z. B. DE-C 2 135 073 ).The emulsion polymerization in the aqueous phase is preferred in the presence of water-soluble initiators and (preferably anionic) emulsifiers (see, for example, US Pat. DE-C 2 135 073 ).

Das Emulsionspolymerisat wird vorzugsweise in Form einer 10- bis 50-gew.-prozentigen, insbesondere 30 bis 40-prozentigen wäßrigen Dispersion erzeugt und angewendet. Für die Verarbeitung ist eine teilweise Neutralisation der Methacrylsäure-Einheiten entbehrlich; sie ist jedoch, beispielsweise in einem Umfang bis zu 5 oder 10 Mol-% möglich, wenn eine Verdickung der Überzugsmitteldispersion erwünscht sein sollte. Der Gewichtsmittelwert der Latex-Teilchengröße beträgt in der Regel 40 bis 100 nm, vorzugsweise 50 bis 70 nm, was eine verarbeitungstechnisch günstige Viskosität unter 1000 mPa · s gewährleistet.The emulsion polymer is preferably produced and used in the form of a 10 to 50% by weight, in particular 30 to 40%, aqueous dispersion. For processing, a partial neutralization of the methacrylic acid units is dispensable; However, it is possible, for example, to an extent of up to 5 or 10 mol%, if thickening of the coating agent dispersion should be desired. The weight average of the latex particle size is usually 40 to 100 nm, preferably 50 to 70 nm, which ensures a processing-technically favorable viscosity below 1000 mPa · s.

Die Schichtdicke des äußeren Überzugs kann z. B. im Bereich von 20 - 150, bevorzugt 40 bis 80 µm liegen.The layer thickness of the outer coating may, for. B. in the range of 20 to 150, preferably 40 to 80 microns.

Mengenverhältnisse innerer/äußerer ÜberzugQuantity ratios inner / outer coating

Das Gesamtgewicht des inneren Überzugs kann bevorzugt 2 bis 50, besonders bevorzugt 10 bis 40 Gew.-% bezogen auf das Gesamtgewicht des Kerns ausmachen.The total weight of the inner coating may preferably be from 2 to 50, particularly preferably from 10 to 40,% by weight, based on the total weight of the core.

Das Gesamtgewicht des Kerns setzt sich aus dem Wirkstoff, den gegebenenfalls zur Formulierung verwendete Hilfsstoffen einschließlich gegebenenfalls verwendeter neutraler Kerne (Non-Pareilles) zusammen, entspricht also dem Trockengewicht der Formulierung.The total weight of the core is composed of the active ingredient, the excipients optionally used for the formulation, including optionally used neutral cores (non-pareilles), thus corresponds to the dry weight of the formulation.

Das Gesamtgewicht des inneren Überzugs setzt sich aus dem Copolymeren und den enthaltenen Hilfsstoffen zusammen, entspricht also dem Trockengewicht der verwendeten Formulierung.The total weight of the inner coating is composed of the copolymer and the auxiliaries contained, thus corresponds to the dry weight of the formulation used.

Das Gesamtgewicht des äußeren Überzugs setzt sich aus dem Copolymeren und den gegebenenfalls enthaltenen Hilfsstoffen, z. B. Weichmacher, zusammen, entspricht also dem Trockengewicht der verwendeten Formulierung.The total weight of the outer coating is composed of the copolymer and the optional excipients, for. As plasticizer, together, so corresponds to the dry weight of the formulation used.

Das Gesamtgewicht des äußeren Überzugs kann bevorzugt 5 bis 50, besonders bevorzugt 10 bis 30 Gew.-% bezogen auf das Gesamtgewicht des Kerns und des inneren Überzugs ausmachen.The total weight of the outer coating may preferably be from 5 to 50, more preferably from 10 to 30, weight percent, based on the total weight of the core and the inner coating.

Im Übrigen zeigen rasterelekronenmikroskopische Aufnahmen von Querschnitten isolierter Doppelfilme mit erfindungsgemäßem Aufbau homogene, gleichmäßige Schichten mit guter Haftung an der Grenzfläche.Incidentally, scanning electron micrographs of cross sections of isolated double films with the structure according to the invention show homogeneous, uniform layers with good adhesion at the interface.

Verfahrenmethod

Die Erfindung betrifft weiterhin ein Verfahren zur Herstellung der erfindungsgemäßen Arzneiform, gekennzeichnet durch die Schritte

  1. a) Erzeugen eines Kerns mit einem pharmazeutischen mittels Sprühauftrag auf einen Neutral-Kern (Non-Pareilles) oder durch Rotagglomeration, Ausfällen, Sprühverfahren oder Extrusion und Spheronisation ohne einen Neutral-Kern herstellt und anschließend
  2. b) Auftragen des inneren Überzugs, mittels Sprühauftrag, so daß wirkstoffhaltige, umhüllte Pellets erhalten werden,
  3. c) Auftragen des äußeren Überzugs, mittels Sprühauftrag, so daß wirkstoffhaltige, zweifach umhüllte Pellets erhalten werden,
  4. d) optional eine abschließende Curing-Behandlung zur Stabilisierung des Freigabeprofils, z. B. durch trockenes Lagern für 2 Stunden bei 40 °C.
The invention further relates to a process for the preparation of the dosage form according to the invention, characterized by the steps
  1. a) producing a core with a pharmaceutical by spray application to a neutral core (non-pareilles) or by Rotagglomeration, precipitation, spraying or extrusion and spheronization without a neutral core produces and then
  2. b) applying the inner coating, by means of spray application, so that active ingredient-containing, coated pellets are obtained,
  3. c) applying the outer coating, by means of spray application, so that active ingredient-containing double-enveloped pellets are obtained,
  4. d) optionally a final curing treatment to stabilize the release profile, e.g. B. by dry storage for 2 hours at 40 ° C.

Die erhaltenen Pellets können mittels pharmazeutisch üblicher Hilfsstoffe und in an sich bekannter Weise zu einer multipartikulären Arzneiform, insbesondere zu pellethaltigen Tabletten, Minitabletten, Kapseln, Sachets oder Trockensäften weiterverarbeitet werden, die so formuliert sind, daß die enthaltenen Pellets im pH-Bereich des Magens freigesetzt werden.The pellets obtained can be further processed by means of pharmaceutically customary auxiliaries and in a manner known per se into a multiparticulate dosage form, in particular pellet-containing tablets, minitablets, capsules, sachets or dry juices, which are formulated so that the pellets contained are released in the pH range of the stomach become.

Multipartikuläre ArzneiformMultiparticulate dosage form

Die erfindungsgemäße Arzneiform, z. B. in Pelletform, kann vorteilhaft als Bestandteil einer multipartikulären Arzneiform verwendet werden. Bei der Verarbeitung in pharmaüblichen Produktionsvorgängen wie Verpressen, Abfüllen in Kapseln bzw. Sachets oder Mischen mit anderen Pelletpräparationen erweisen sich die verbesserten mechanischen Eigenschaften als besonders vorteilhaft. Die Vorteile treten insbesondere bei sehr dünnen Überzügen und/oder sehr hoher Wirkstoffbeladung hervor. Gerade bei Verpressen von Pellets zu Tabletten, wo besonders hohe mechanische Kräfte auftreten, erweist sich die erfindungsgemäße Arzneiform als wenig anfällig gegenüber Beschädigungen der Überzugsschichten. Die Folge ist eine hohe Prozesssicherheit und eine hohe Reproduzierbarkeit der Eigenschaften von Einheiten aus verschiedenen Produktionszyklen.The dosage form according to the invention, for. B. in pellet form, can be advantageously used as part of a multiparticulate dosage form. When processed in pharmaceutical production processes such as compression, filling in capsules or sachets or mixing with other pellet preparations, the improved mechanical properties prove to be particularly advantageous. The advantages are particularly evident in very thin coatings and / or very high drug loading. Especially when compressing pellets into tablets, where particularly high mechanical forces occur, the dosage form according to the invention proves to be less susceptible to damage to the coating layers. The result is high process reliability and high reproducibility of the properties of units from different production cycles.

Freisetzungscharakteristikrelease characteristics

Die Wirkstofffreisetzungscharakteristik entspricht zwar nicht exakt derjenigen, er WO 01/68058 ist jedoch ähnlich. Die Abweichungen sind überraschend gering. Die Arzneiform eignet sich daher besonders gut für die Freisetzung von Wirkstoffen im Colon.The drug release characteristic is not exactly the same as it WO 01/68058 is however similar. The deviations are surprisingly low. The drug form is therefore particularly well suited for the release of active ingredients in the colon.

Im Freisetzungstest nach USP für zwei Stunden bei pH 1,2 und anschließendem Umpuffern auf pH 7,0 den enthaltenen Wirkstoff im Zeitraum bis 2,0 Stunden nach Testbeginn zu weniger als 5 % und zum Zeitpunkt acht Stunden nach Testbeginn zu 30 bis 80 %, insbesondere zu 40 bis 70 % freisetzt.In the release test according to USP for two hours at pH 1.2 and subsequent rebuffering to pH 7.0 the active ingredient contained in the period up to 2.0 hours after the start of the test to less than 5% and at the time point eight Hours after the start of the test to 30 to 80%, in particular 40 to 70% releases.

Der Freisetzungstest z. B. nach USP (nach USP XXIV, Methode B, modifizierter Test für "enteric coated products") ist dem Fachmann bekannt. Die Versuchsbedingungen sind insbesondere: Paddle-Methode, 100 Umdrehungen pro Minute, 37 °C; pH 1,2 mit 0,1 N HCl, pH 7,0 durch Zugabe von 0,2 M Phosphatpuffer und Einstellen mit 2 N NaOH. Siehe auch USP 27-NF22 Supplement 1, Methode "Delayed Release" Monographie <724> Drug Release.The release test z. B. USP (according to USP XXIV, method B, modified test for "enteric coated products") is known in the art. The test conditions are in particular: Paddle method, 100 revolutions per minute, 37 ° C; pH 1.2 with 0.1 N HCl, pH 7.0 by addition of 0.2 M phosphate buffer and adjusting with 2 N NaOH. See also USP 27-NF22 Supplement 1, Method "Delayed Release" Monograph <724> Drug Release.

Die zu verwendende mehrschichtige Arzneiform besteht im wesentlichen aus einem Kern mit einem Wirkstoff, einem inneren und einem äußeren Überzug. In üblicher Weise können pharmazeutisch gebräuchliche Hilfsstoffe enthalten sein, die aber für die Erfindung nicht kritisch sind.The multi-layered dosage form to be used consists essentially of a core with an active ingredient, an inner and an outer coating. In the usual way, pharmaceutically acceptable excipients may be included, but are not critical to the invention.

Pharmazeutische WirkstoffePharmaceutical agents

Die im Sinne der Erfindung einsetzbaren pharmazeutischen Wirkstoffe sind dazu bestimmt, am oder im menschlichen oder tierischen Körper Anwendung zu finden, um

  1. 1. Krankheiten, Leiden, Körperschäden oder krankhafte Beschwerden zu heilen, zu lindern, zu verhüten oder zu erkennen.
  2. 2. die Beschaffenheit, den Zustand oder die Funktionen des Körpers oder seelische Zustände erkennen lassen.
  3. 3. vom menschlichen oder tierischen Körper erzeugte Wirkstoffe oder Körperflüssigkeiten zu ersetzen.
  4. 4. Krankheitserreger, Parasiten oder körperfremde Stoffe abzuwehren, zu beseitigen oder unschädlich zu machen oder
  5. 5. die Beschaffenheit, den Zustand oder die Funktionen des Körpers oder seelische Zustände zu beeinflussen.
Gebräuchliche Arzneistoffe sind Nachschlagewerken, wie z.B. der Roten Liste oder dem Merck Index zu entnehmen. Beispielhaft seien 5-Aminosalicylsäure, Corticosteroide (Budesonid), sowie Proteine (Insulin, Hormone, Antikörper) angeführt. Erfindungsgemäß können alle Wirkstoffe eingesetzt werden, die die gewünschte therapeutische Wirkung im Sinne der obigen Definition erfüllen und eine ausreichende Stabilität besitzen und deren Wirksamkeit gemäß der obigen Punkte über das Colon erreicht werden kann.
Wichtige Beispiele (Gruppen und Einzelsubstanzen) ohne Anspruch auf Vollständigkeit sind folgende:
  • Analgetika, Antibiotika, Antidiabetika, Antikörper
  • Chemotherapeutika, Corticoide/Corticosteroide
  • Entzündungshemmende Mittel, Enzympräparate
  • Hormone und deren Hemmstoffe, Nebenschilddrüsenhormone
  • Verdauungsfördernde Mittel, Vitamine, Zytostatika
The pharmaceutical active substances which can be used for the purposes of the invention are intended to be used on or in the human or animal body
  1. 1. To cure, alleviate, prevent or recognize diseases, ailments, physical injuries or pathological complaints.
  2. 2. Recognize the nature, condition or functions of the body or mental states.
  3. 3. to replace active substances or body fluids produced by the human or animal body.
  4. 4. to ward off, eliminate or neutralize pathogens, parasites or foreign substances, or
  5. 5. to influence the nature, condition or functions of the body or mental states.
Common drugs can be found in reference books such as the Red List or the Merck Index. Examples include 5-aminosalicylic acid, corticosteroids (budesonide), and proteins (insulin, hormones, antibodies) are listed. According to the invention, it is possible to use all active ingredients which fulfill the desired therapeutic effect in the sense of the above definition and have sufficient stability and whose effectiveness according to the above points can be achieved via the colon.
Important examples (groups and individual substances) without claim of completeness are the following:
  • Analgesics, antibiotics, antidiabetics, antibodies
  • Chemotherapeutics, corticoids / corticosteroids
  • Anti-inflammatories, enzyme preparations
  • Hormones and their inhibitors, parathyroid hormones
  • Digestive agents, vitamins, cytostatics

Als Wirkstoffe sind insbesondere solche zu nennen, die im Darm, insbesondere kurz vor oder erst im Dickdarmbereich möglichst konstant freigesetzt werden sollen. Somit kann der pharmazeutische Wirkstoff ein Aminosalicylat, ein Sulfonamid oder ein Glucocorticoid sein, insbesondere 5-Aminosalicylsäure, Olsalazin, Sulfalazin, Prednison oder Budesonid.As active ingredients are in particular to be mentioned, which should be released as constantly as possible in the intestine, especially shortly before or only in the colon. Thus, the pharmaceutical agent may be an aminosalicylate, a sulfonamide or a glucocorticoid, in particular 5-aminosalicylic acid, olsalazine, sulfalazine, prednisone or budesonide.

Beispiele für WirkstoffeExamples of active ingredients

  • Mesalazinmesalazine
  • Sulfasalazinsulfasalazine
  • Bethamethason-21-dihydrogenophosphatBethamethason-21 dihydrogenophosphat
  • Hydrocortison-21-acetatHydrocortisone 21-acetate
  • Cromoglicinsäurecromolyn
  • Dexamethasondexamethasone
  • Olsalazin-NaOlsalazine-Na
  • Budesonid, PrednisonBudesonide, prednisone
  • Bismunitrat, Karaya GummiBismunitrate, Karaya gum
  • Methylprednisolon-21-hydrogensuccinatMethylprednisolone 21-succinate
  • Myhrre, Kaffeekohle, KamillenblüttenextraktMyhrre, coffee charcoal, chamomile extract
  • 10% Suspension von Humanplacenta10% suspension of human placenta
Neuere Wirkstoffe, bzw. Wirkstoffe in der Entwicklung und PrüfungNewer agents, or agents in development and testing

(Literatur aus einschlägigen, dem Fachmann bekannten pharmazeutischen Datenbanken)(Literature from relevant pharmaceutical databases known to the person skilled in the art)

  • Balsalazidbalsalazide
  • Oral verabreichte Peptide (z.B. RDP 58)Orally administered peptides (e.g., RDP 58)
  • Interleukin 6Interleukin 6
  • Interleukin 12Interleukin 12
  • Ilodecakin (Interleukin 10)Ilodecacin (Interleukin 10)
  • Nicotintartratnicotine tartrate
  • 5-ASA Konjugate (CPR 2015)5-ASA conjugates (CPR 2015)
  • Monoclonaler Antikörper gegen Interleukin 12Monoclonal antibody against interleukin 12
  • Diethyldihydroxyhomospermin (DEHOHO)Diethyldihydroxyhomospermine (DEHOHO)
  • Diethylhomospermin (DEHOP)Diethyl homospermine (DEHOP)
  • Cholecystokinin (CCK) Antagonist (CR 1795)Cholecystokinin (CCK) antagonist (CR 1795)
  • 15 Aminosäure-Fragment eines 40 kd Peptids aus Magensaft (BPC 15)15 amino acid fragment of a 40 kd peptide from gastric juice (BPC 15)
  • Glucocorticoidanalogon (CBP 1011)Glucocorticoid analogue (CBP 1011)
  • Natalizumabnatalizumab
  • Infliximab (REMICADE)Infliximab (REMICADE)
  • N-de-Acetyliertes Lysoglycosphingolipid (WILD 20)N-de-acetylated lysoglycosphingolipid (WILD 20)
  • AzelastineAzelastine
  • Tranilasttranilast
  • SudismaseSudismase
  • Phosphorothioat Antisensoligonucleotid (ISIS 2302)Phosphorothioate Antisense oligonucleotide (ISIS 2302)
  • TazofeloneTazofelone
  • Ropivacaineropivacaine
  • 5 Lipoxygenaseinhibitor (A 69412)5 Lipoxygenase inhibitor (A 69412)
  • Sucralfatsucralfate

Die Arzneiform kann einen pharmazeutischen Wirkstoff enthalten, der ein Enzym, ein Peptidhormon, ein immunmodulatorisches Protein, ein Antigen oder Antikörper ist.The dosage form may contain a pharmaceutical agent which is an enzyme, a peptide hormone, an immunomodulatory protein, an antigen or antibody.

Die Arzneiform kann als pharmazeutischen Wirkstoff ein Pankreatin, ein Insulin, ein Human Growth Hormon (hGH), Corbaplatin, Intron A, Calcitonin, Cromalyn, ein Interferon, ein Calcitonin, Granulocyte Colony Stimulating factor (G-CSF), ein Interleukin, Parathyroidhormone, Glucagon, Pro-Somatostatin, ein Somatostatin, Detirelix, Cetrorelix, Vasopressin, 1-Deaminocysteine-8-D-arginine-Vasopressin, Leuprolidacetat oder ein Antigen, das aus Gräsern oder anderen Pflanzen, wie z. B. Roggen, Weizen, Gerste, Hafer, Bermuda Gras, Zinnkraut, Ahorn, Ulme, Eiche, Platane, Pappel, Zeder, Zinnkraut, Disteln gewonnen wurde, enthalten.The pharmaceutical form may contain as pharmaceutical active substance a pancreatin, an insulin, a human growth hormone (hGH), corbaplatin, intron A, calcitonin, cromaline, an interferon, a calcitonin, granulocyte colony stimulating factor (G-CSF), an interleukin, parathyroid hormones, Glucagon, pro-somatostatin, a somatostatin, detirelix, cetrorelix, vasopressin, 1-deaminocysteine-8-D-arginine vasopressin, leuprolide acetate or an antigen derived from grasses or other plants such as e.g. As rye, wheat, barley, oats, bermuda grass, horsetail, maple, elm, oak, sycamore, poplar, cedar, horsetail, thistles was obtained.

Pharmazeutisch übliche HilfsstoffePharmaceutically customary excipients

Von den pharmazeutisch übliche Hilfsstoffen im Sinne der Erfindung sind Porenbildner in Mengenanteilen ab 5 Gew.-%, bezogen auf den inneren Überzug ausgenommen.Of the pharmaceutically customary excipients in the context of the invention, pore formers are excluded in amounts from 5% by weight, based on the inner coating.

Bei der Herstellung der mehrschichtigen Arzneiform können pharmazeutisch übliche Hilfsstoffe in üblicher Weise eingesetzt werden.In the preparation of the multilayer drug form, pharmaceutically customary auxiliaries can be used in the customary manner.

Trockenstellmittel (Antihaftmittel): Trockenstellmittel haben folgende Eigenschaften: sie verfügen über große spezifische Oberflächen, sind chemisch inert, sind gut rieselfähig und feinteilig. Aufgrund dieser Eigenschaften erniedrigen sie die Klebrigkeit von Polymeren, die als funktionelle Gruppen polare Comonomere enthalten. Dry-action agents (anti-adhesive agents): Dry-action agents have the following properties: they have large specific surfaces, are chemically inert, have good free-flowing properties and are finely divided. Based on these Properties reduce the tackiness of polymers containing as functional groups polar comonomers.

Beispiele für Trockenstellmittel sind:Examples of dryers are:

Aluminiumoxid, Magnesiumoxid, Kaolin, Talkum, Glycerolmonostearat, Magnesiumstearat, Kieselsäure (Aerosile), Syloid, Bariumsulfat.Alumina, magnesia, kaolin, talc, glycerol monostearate, magnesium stearate, silicic acid (aerosils), syloid, barium sulfate.

Trennmittelrelease agent

Beispiele für Trennmittel sind:

  • Ester von Fettsäuren oder Fettsäureamide , aliphatische, langkettige Carbonsäuren, Fettalkohole sowie deren Ester, Montan- oder Paraffinwachse und Metallseifen, insbesondere zu nennen sind Glycerolmonostearat, Stearylalkohol, Glycerolbehensäureester, Cetylalkohol, Palmitinsäure, Kanaubawachs, Bienenwachs etc.. Übliche Mengenanteile liegen im Bereich von 0,05 Gew-% bis 5, bevorzugt 0,1 bis 3 Gew.-% bezogen auf das Copolymere.
Examples of release agents are:
  • Esters of fatty acids or fatty acid amides, aliphatic, long-chain carboxylic acids, fatty alcohols and their esters, montan or paraffin waxes and metal soaps, in particular glycerol monostearate, stearyl alcohol, Glycerolbehensäureester, cetyl alcohol, palmitic acid, Kanaubawachs, beeswax etc .. Usual proportions are in the range of 0 , 05% by weight to 5, preferably 0.1 to 3 wt .-% based on the copolymer.

Weitere pharmazeutisch übliche Hilfsstoffe: Hier sind z. B, Stabilisatoren, Farbstoffe, Antioxidantien, Netzmittel, Pigmente, Glanzmittel etc. zu nennen. Sie dienen vor allem als Verarbeitungshilfsmittel und sollen ein sicheres und reproduzierbares Herstellungsverfahren sowie gute Langzeitlagerstabilität gewährleisten werden kann. Weitere pharmazeutisch übliche Hilfsstoffe können in Mengen von 0,001 Gew-% bis 30 Gew.-%, bevorzugt 0,1 bis 10 Gew.-% bezogen auf das Copolymere vorliegen. Other pharmaceutically customary excipients: Here are z. B, stabilizers, dyes, antioxidants, wetting agents, pigments, brighteners, etc. They serve primarily as a processing aid and should be able to ensure a safe and reproducible production process and good long-term storage stability. Other pharmaceutically customary auxiliaries can be present in amounts of from 0.001% by weight to 30% by weight, preferably from 0.1 to 10% by weight, based on the copolymer.

Weichmacher: Als Weichmacher geeignete Stoffe haben in der Regel ein Molekulargewicht zwischen 100 und 20 000 und enthalten eine oder mehrere hydrophile Gruppen im Molekül, z. B. Hydroxyl- , Ester- oder Aminogruppen. Geeignet sind Citrate, Phthalate, Sebacate, Rizinusöl. Beispiele geeigneter Weichmacher sind Citronensäurealkylester, Glycerinester, Phthalsäurealkylester, Sebacinsäurealkylester, Sucroseester, Sorbitanester, Dibutylsebacat und Polyethylenglykole 4000 bis 20.000. Bevorzugte Weichmacher sind Tributylcitrat, Triethylcitrat, Acetyltriethylcitrat, Dibutylsebacat und Diethylsebacat. Die Einsatzmengen liegen zwischen 1 und 35, bevorzugt 2 bis 10 Gew.-%, bezogen auf das jeweilige Polymer oder Copolymer. Plasticizers: Substances suitable as plasticizers generally have a molecular weight between 100 and 20,000 and contain one or more hydrophilic groups in the molecule, eg. B. hydroxyl, ester or amino groups. Suitable are citrates, phthalates, sebacates, castor oil. Examples of suitable Plasticizers are citric acid alkyl esters, glycerol esters, alkyl phthalates, sebacic acid alkyl esters, sucrose esters, sorbitan esters, dibutyl sebacate and polyethylene glycols 4000 to 20,000. Preferred plasticizers are tributyl citrate, triethyl citrate, acetyl triethyl citrate, dibutyl sebacate and diethyl sebacate. The amounts used are between 1 and 35, preferably 2 to 10 wt .-%, based on the respective polymer or copolymer.

Applikationsformenapplication forms

Die beschriebene Arzneiform kann als überzogene Tablette, in Form einer Tablette aus verpreßten Pellets oder in Form von Pellets vorliegen, die in eine Kapsel, z. B. aus Gelatine, Stärke oder Cellulosederivaten, eingefüllt sind.The dosage form described may be in the form of a coated tablet, in the form of a compressed pellet pellet or in the form of pellets which are placed in a capsule, e.g. As gelatin, starch or cellulose derivatives are filled.

BEISPIELEEXAMPLES Prüfung mechanischer Eigenschaften von 1- und 2-schichtigen Filmüberzügen, die durch Ausgießen hergestellt wurdenTesting mechanical properties of 1- and 2-layer film coatings prepared by pouring

EUDRAGIT® RS: Copolymer aus 65 Gew.-% Methylmethacrylat, 30 Gew.-% Ethylacrylat und 5 Gew.-% 2-Trimethylammoniumethylmethacrylat-Chlorid.EUDRAGIT ® RS: copolymer of 65 wt .-% methyl methacrylate, 30 wt .-% ethyl acrylate and 5 wt .-% of 2-trimethylammoniumethyl methacrylate chloride.

EUDRAGIT® RL: Copolymer aus 6 Gew.-% Methylmethacrylat, 30 Gew.-% Ethylacrylat und 10 Gew.-% 2-Trimethylammoniumethylmethacrylat-Chlorid.EUDRAGIT ® RL: copolymer of 6 wt .-% methyl methacrylate, 30 wt .-% ethyl acrylate and 10 wt .-% of 2-trimethylammoniumethyl methacrylate chloride.

EUDRAGIT® NE: Copolymer aus 30 Gew.-% Ethylacrylat und 70 Gew.-% Methylmethacrylat.EUDRAGIT ® NE: copolymer of 30 wt .-% ethyl acrylate and 70 wt .-% methyl methacrylate.

EUDRAGIT® FS: Copolymer aus 65 Gew.-% Methylacrylat, 25 Gew.-% Methylmethacrylat und 10 Gew.-% Methacrylsäure

  1. 1. Schicht = entspricht dem inneren Überzugsfilm in einer erfindungsgemäßen Arzneiform
  2. 2. Schicht = entspricht dem äußeren Überzugsfilm in einer erfindungsgemäße Arzneiform
EUDRAGIT ® FS: copolymer of 65 wt .-% of methyl acrylate, 25 wt .-% methyl methacrylate and 10 wt .-% methacrylic acid
  1. 1st layer = corresponds to the inner coating film in a dosage form according to the invention
  2. 2nd layer = corresponds to the outer coating film in a dosage form according to the invention

Herstellung der filmbildenden Formulierungen:Preparation of film-forming formulations: EUDRAGIT® FS 30 D Formulierung, 10 %-ig wässrig,EUDRAGIT ® FS 30 D formulation, 10% aqueous,

hergestellt aus einer 30 % igen EUDRAGIT FS 30 D Dispersion und 5 % (bezogen aufs Polymere) Triethylcitrat (TEC), mit deionisiertem Wasser wird die Dispersion auf 10 % verdünnt:
Im einem 400 ml Becherglas wurden TEC und Wasser eingewogen und bei 400 UpM auf dem Magnetrührer bis zur Auflösung des TEC gerührt bis zur klaren Lösung.
In einer 500 ml PE-Schraubflasche wird die über ein ca. 0,1 bis 0,2 mm Metallsieb filtrierte Menge von EUDRAGIT® FS 30 D vorgelegt und unter Rührung mit dem Magnetrührer bei ca. 400 ± 100 UpM die wässrige TEC-Lösung dazugegeben.
Die Formulierung wird verschlossen bei Raumtemperatur mindestens
1 - 2 Stunden bei dieser Drehzahl gerührt.
Die 10 %-ige Dispersion wurde über Nacht im Kühlschrank bei 4 - 8°C gelagert werden und am nächsten Tag kurz vorm Ausgießen auf die Platte aufgerührt.prepared from a 30% EUDRAGIT FS 30 D dispersion and 5% (based on the polymer) triethyl citrate (TEC), with deionized water, the dispersion is diluted to 10%:
In a 400 ml beaker TEC and water were weighed and stirred at 400 rpm on the magnetic stirrer until the dissolution of the TEC until a clear solution.
In a 500 ml PE-Schraubflasche the mixture was filtered through an approximately 0.1 to 0.2 mm metal sieve amount of EUDRAGIT ® FS 30 D is provided thereto and the aqueous TEC solution while stirring with the magnetic stirrer at about 400 rpm ± 100 ,
The formulation is sealed at room temperature at least
Stirred for 1 - 2 hours at this speed.
The 10% dispersion was stored overnight in the refrigerator at 4-8 ° C and stirred the next day shortly before pouring onto the plate.

EUDRAGIT® RS 30 D / RL 30 D (1:1)Formulierung, 10 % ig wässrig,EUDRAGIT ® RS 30 D / RL 30 D (1: 1) formulation, 10% aqueous,

hergestellt aus einer Mischung von jeweils 30 %-igen
EUDRAGIT® RS 30 D / RL 30D (1:1) Dispersion und 20 % (bezogen aufs Polymere) Triethylcitrat, mit deionisiertem Wasser wird die Dispersion auf 10 % verdünnt:made from a mixture of 30% each
EUDRAGIT ® RS 30 D / RL 30D (1: 1) dispersion and 20% (based on polymer) triethylcitrate, with deionized water, the dispersion is diluted to 10%:

Im einem 400 ml Becherglas wurden TEC und Wasser eingewogen und bei 500 Upm auf dem Magnetrührer bis zur Auflösung des TEC gerührt bis zur klaren Lösung.
In einer 500 ml PE-Schraubflasche wird die über ein ca. 0,1 bis 0,2 mm Metallsieb filtrierte Menge von EUDRAGIT® RS 30 D / RL 30D (1:1) Dispersion vorgelegt und unter Rührung mit dem Magnetrührer bei ca. 400 ± 100 Upm die wässrige TEC-Lösung dazugegeben.
Die Formulierung wird verschlossen bei Raumtemperatur über Nacht bei dieser Drehzahl gerührt.In a 400 ml beaker TEC and water were weighed and stirred at 500 rpm on the magnetic stirrer until the dissolution of the TEC to a clear solution.
In a 500 ml PE-Schraubflasche the mixture was filtered through an approximately 0.1 to 0.2 mm metal sieve amount of EUDRAGIT ® RS 30 D / RL 30D (1: 1) and submitted to dispersion with agitation with the magnetic stirrer at about 400 ± 100 rpm, add the aqueous TEC solution.
The formulation is stirred at room temperature overnight at this speed.

EUDRAGIT®NE 30D Formulierung, 10 % ig wässrig,EUDRAGIT ® NE 30D formulation, 10% aqueous,

hergestellt aus einer 30 % igen EUDRAGIT® NE 30 D Dispersion und verdünnt mit deionisiertem Wasser auf 10 % verdünnt:
In einer 500 ml PE-Schraubflasche wird die über ein ca. 0,1 bis 0,2 mm Metallsieb filtrierte Menge von EUDRAGIT® NE 30 D vorgelegt und unter Rührung mit dem Magnetrührer bei ca. 400 ± 100 UpM das Wasser dazugegeben.
Die Formulierung wird verschlossen bei Raumtemperatur über Nacht bei dieser Drehzahl gerührt.prepared from a 30% EUDRAGIT ® NE 30 D dispersion and diluted with deionized water to 10% diluted:
In a 500 ml PE-Schraubflasche the mixture was filtered through an approximately 0.1 to 0.2 mm metal sieve amount of EUDRAGIT ® NE 30 D and is presented thereto under stirring with the magnetic stirrer at about 400 rpm ± 100 the water.
The formulation is stirred at room temperature overnight at this speed.

Polyvinylacetat (Kollicoat® SR 30 D) Formulierung, 10 % ig wässrig,Polyvinyl acetate (Kollicoat ® SR 30 D) formulation, 10% aqueous,

hergestellt aus einer 30 %-igen Polyvinylacetat Dispersion, 10 % (bezogen aufs Polymere) Propylenglykol und 3 % (bezogen aufs Polymere) Kollidon® 25, mit deionisiertem Wasser wird die Dispersion auf 10 % verdünnt:
Im einem 400 ml Becherglas wurden Propylenglykol und Wasser eingewogen und bei 500 Upm auf dem Magnetrührer bis zur Auflösung des Propylenglykols gerührt.
Kollidon® 25 wird dann bei Rührgeschwindigkeit von anfangs 300 bis später 990 Upm eingetragen und solange gerührt bis Kollidon 25 benetzt ist. Verklumpungen werden anschließend mit Hilfe eines Ultraturrax-Rührers ca. 15 min lang bei ca. 900 Upm Rührung aufgelöst. Die klare Lösung wird anschließend zur Luftblasenentweichung
5 min bei Raumtemperatur stehen gelassen.
In einer 500 ml PE-Schraubflasche wird die über ein ca. 0,1 bis 0,2 mm Metallsieb filtrierte Menge der Polyvinylacetat Dispersion vorgelegt und unter Rührung mit dem Magnetrührer bei ca. 400 ± 100 UpM die wässr. Propylenglykol - Kollidon® 25 - Lösung dazugegeben.prepared from a 30% polyvinyl acetate dispersion, 10% (based on the polymer) propylene glycol and 3% (based on the polymer) Kollidon ® 25, with deionized water, the dispersion is diluted to 10%:
In a 400 ml beaker propylene glycol and water were weighed and stirred at 500 rpm on the magnetic stirrer until the dissolution of the propylene glycol.
Kollidon ® 25 is then introduced at stirring speed of initially 300 to 990 rpm, and subsequently is wetted mixture is stirred until Kollidon 25th Clumps are then dissolved with the aid of an Ultraturrax stirrer for about 15 minutes at about 900 rpm stirring. The clear solution then becomes air bubble leakage
Allowed to stand for 5 min at room temperature.
The amount of polyvinyl acetate dispersion filtered through an approximately 0.1 to 0.2 mm metal sieve is placed in a 500 ml PE screw-type bottle and the aq. Stirred at about 400 ± 100 rpm while stirring with the magnetic stirrer. Propylene glycol - Kollidon ® 25 solution added.

Die Formulierung wird verschlossen bei Raumtemperatur über Nacht bei dieser Drehzahl gerührt.The formulation is stirred at room temperature overnight at this speed.

FilmeausgießenFilmeausgießen Vorbereitung der Ausgussplatten:Preparation of the spout plates:

20 cm x20 cm große Glasplatten werden mit einem 2 cm Gewebeklebeband am Rand 3lagig abgeklebt, so dass man eine Umrandung von ca. 1 mm Höhe erhält und eine Ausguss-Innenfläche von ca. 256 cm2.20 cm x 20 cm large glass plates are taped 3-ply with a 2 cm tissue tape on the edge, so that you get a border of about 1 mm in height and a spout inner surface of about 256 cm 2 .

Die ca. 256 cm2 Ausguss-Innenfläche der Glasplatte wird dann mit einem Haftkleber einmal bepinselt und mit einem Warmluftfön angetrocknet.The approximately 256 cm 2 spout inside surface of the glass plate is then brushed with a pressure-sensitive adhesive once and dried with a hot air dryer.

Auf diese klebrige Fläche wird nun eine 20 cm x 20 cm große Aluminiumfolie von
Fa. TSCHELLIN mit der Mattseite nach oben beklebt, d.h. darauf glatt gewalzt oder mit einem Kuchenschaber bis in die Eckkanten glatt ausgestrichen. (Aluminiumfolie = 0,012 mm Dickenstärke, Seiten = glänzend/mattweich, Mattseite= lackkaschierte auf gefärbte biaxial gereckte Polypropylenfolie 0,03 mm).
Die über den Rand nichtklebende Aluminiumfolie wird nach oben gebogen, so dass man nun einen erhöhte Umrandungsfläche hat, die ein Überlaufen der Flüssigkeit verhindern kann.On this sticky surface is now a 20 cm x 20 cm large aluminum foil of
Fa. TSCHELLIN stuck with the matte side facing upwards, ie rolled smoothly or even smoothed out to the corner edges with a cake scraper. (Aluminum foil = 0.012 mm thickness, sides = glossy / matt soft, matt side = lacquer-coated on dyed biaxially stretched polypropylene foil 0.03 mm).
The non-adhesive aluminum foil over the edge is bent upwards, so that one now has an increased peripheral surface, which can prevent overflow of the liquid.

Die so präparierten Ausguss-Glasplatten werden nun im Umlufttrockenschrank mit einer Libelle waagegerecht austariert ausgelegt.The spouted glass plates prepared in this way are now balanced in a circulating air drying cabinet with a spirit level.

Herstellung 2-schichtiger Filme:Production of 2-layer films:

Alle hergestellten Formulierungen werden vor dem Ausgießen zur Filmherstellung jeweils über ein ca. 0,1 bis 0,2 mm Metallsieb filtriert.All formulations prepared are each filtered over a 0.1 to 0.2 mm metal mesh prior to pouring for film production.

Auf die präparierten und im Umlufttrockenschrank austarierten Ausguss-Glasplatten werden als 1. Grundschicht pro Platte jeweils 64 g einer über ein Metallsieb filtrierten
10 % igen EUDRAGIT® FS 30 D Formulierung bei Raumtemperatur ausgegossen. Erst dann wird der Umlufttrockenschrank auf 50 °C geheizt und die Filme bei dieser Temperatur mit minimaler Ventilatorumdrehung und einer 30% geöffneten Luftklappe mindestens 3 Tage getrocknet.
Die nun klar aussehenden teilweise glatten FS 30 D - Filme werden nun im geöffneten Umlufttrockenschrank auf Raumtemperatur abgekühlt, bevor die 2. Filmschicht ausgegossen wird.
Pro EUDRAGIT® - bzw. Konkurrenzprodukt- Probe werden 3 Ausguss-Glasplatten mit EUDRAGIT® FS 30 D - Filmen als 1. Grundschicht verwendet. Auf diese EUDRAGIT® FS 30 D - Filmgrundschicht wird nun jeweils 64 g einer über ein Metallsieb filtrierten 10 %-igen EUDRAGIT® - bzw. anderen Probe ausgegossen.
Auch hier wird erst dann nach dem Ausgießen der Formulierungen der Umlufttrockenschrank auf 50 °C geheizt und die Filme bei dieser Temperatur mit minimaler Ventilatorumdrehung und einer 30% geöffneten Luftklappe mindestens 3 bis 5 Tage getrocknet bis die Filme ein klares Aussehen erhalten, Ausnahme: 2-schichtiger Film mit Polyvinylacetat (Kollicoat® SR 30 D) zeigt eine leicht gelblich milchige Trübung (5 Tage-Trocknung) und mit Ethylcellulose (Aquacoat® ECD-30) eine leicht rissige Trübung mit Haftungsproblemen zum Unterfilm (3 Tage-Trocknung).On the prepared spouted glass plates, which have been tared in a circulating air drying cabinet, 64 g of each are filtered through a metal sieve as the first base layer per plate
10% EUDRAGIT ® FS 30 D formulation poured out at room temperature. Only then is the convection oven heated to 50 ° C and the films dried at this temperature with minimal fan rotation and a 30% open air damper for at least 3 days.
The now clear - looking, partially smooth FS 30 D films are now cooled to room temperature in the open convection oven before the second film layer is poured out.
For each EUDRAGIT ® or competing product sample, 3 spout glass plates with EUDRAGIT ® FS 30 D films are used as the first base layer. In this EUDRAGIT ® FS 30 D - film base layer each 64 g of a filtered through a metal is now 10% EUDRAGIT ® - or poured other sample.
Again, after the pouring of the formulations of the convection oven is heated to 50 ° C and the films at this temperature with minimal fan rotation and a 30% open air damper dried at least 3 to 5 days until the films get a clear appearance, except: 2- layered film having polyvinyl acetate (Kollicoat ® SR 30 D) shows a slightly yellowish milky turbidity (5 days drying) and ethyl cellulose (Aquacoat ® ECD 30) has a slightly cracked turbidity problems of adhesion to the lower film (3 days drying).

Die nun erhaltenen 2-schichtigen Filme werden auf Raumtemperatur abgekühlt, vorsichtig von der Aluminiumfolie gelöst und jeder für sich in Filterpapier geformte Taschen aufbewahrt, die wiederum in einem PE-Beutel eingeschweißt werden.The 2-ply films now obtained are cooled to room temperature, carefully detached from the aluminum foil, and each stored individually in filter paper bags, which in turn are sealed in a PE bag.

Herstellung 1-schichtiger Filme:Production of 1-layer films:

Alle hergestellten Formulierungen werden vor dem Ausgießen zur Filmherstellung jeweils über ein ca. 0,1 bis 0,2 mm Metallsieb filtriert.All formulations prepared are each filtered over a 0.1 to 0.2 mm metal mesh prior to pouring for film production.

Auf die präparierten und im Umlufttrockenschrank austarierten Ausguss-Glasplatten werden pro Probe je 2 Platten mit jeweils 100 g einer über ein Metallsieb filtrierten
10 % igen EUDRAGIT® - bzw. Konkurrenzprodukt -Formulierung bzw. 67 g einer über ein Metallsieb filtrierten 15 % igen Formulierung (z.B. kolloidale Lösung von Formulierung) bei Raumtemperatur ausgegossen.
Erst dann wird der Umlufttrockenschrank auf 50 °C geheizt und die Filme bei dieser Temperatur mit minimaler Ventilatorumdrehung und einer 30% geöffneten Luftklappe mindestens 3 Tage getrocknet. Nach dieser Zeit zeigen die Filme von der Formulierung EUDRAGIT® FS 30 D und EUDRAGIT® NE 30 D ein klares Aussehen, Aquacoat® ECD-30 ergibt einen sehr spröden Film, der schon bei der Handhabung zerbricht und somit nicht mehr bestimmbar ist. Filmformulierungen von Kollicoat® SR 30 D und EUDRAGIT® RS 30 D / RL 30 D (1:1) können nach 3 Tagen nochmals bei 60 °C über Nacht zur Entfernung der Restfeuchte temperiert werden. Dabei muss auf Blasenbildung geachtet werden. Das Aussehen bei EUDRAGIT® RS 30 D / RL 30 D (1:1) ist dann klar bis minimal trüb und bei Kollicoat® SR 30 D gelblich trüb.
Die nun erhaltenen 1-schichtigen Filme werden auf Raumtemperatur abgekühlt, vorsichtig von der Aluminiumfolie gelöst und jeder für sich in Filterpapier geformte Taschen aufbewahrt, die wiederum in einen PE-Beutel eingeschweißt werden.On the prepared and in the circulating air drying oven balanced Ausguss glass plates are per sample 2 plates each with 100 g of filtered through a metal sieve
10% EUDRAGIT ® - or competing product formulation and 67 g of a filtered through a metal sieve 15% formulation (eg colloidal solution of formulation) poured at room temperature.
Only then is the convection oven heated to 50 ° C and the films dried at this temperature with minimal fan rotation and a 30% open air damper for at least 3 days. After this time, the films of the formulation EUDRAGIT ® FS 30 D and EUDRAGIT ® NE 30 D have a clear appearance, Aquacoat ® ECD-30 results in a very brittle film, which breaks even during handling and is thus no longer determinable. Film formulations of Kollicoat ® SR 30 D and EUDRAGIT ® RS 30 D / RL 30 D (1: 1) can be tempered again after 3 days at 60 ° C overnight to remove the residual moisture. Care must be taken to blister. The appearance on EUDRAGIT ® RS 30 D / RL 30 D (1: 1) is then clear to slightly hazy and in Kollicoat ® SR 30 D yellowish cloudy.
The 1-layer films now obtained are cooled to room temperature, carefully detached from the aluminum foil and each individually in filter paper stored shaped bags, which are in turn welded into a PE bag.

Zugversuch:Tensile test:

Vorschrift:rule: ISO 527-2 /1BA / 20ISO 527-2 / 1BA / 20 Prüfklima:Test conditions: 23°C / 50 % rel. F.23 ° C / 50% rel. F. Spannzeug:Fixture: Luftair Maschine:Machine: Genauigkeitsklasse 1 %Accuracy class 1% Wegaufnehmer:transducer: Traversetraverse Einspannlänge:clamping: 57,5 mm57.5 mm Konditionierung:conditioning: 16 Std. Normklima (23°C / 50 % rel. F.)16 hours standard climate (23 ° C / 50% rel. Messlänge:Measuring length: 57,5 mm57.5 mm Vorlast:preload: 0,05 MPa0.05 MPa

Beispiel 1-10Example 1-10

Bsp.Ex. Polymerepolymers Zugfestigkeittensile strenght Nom. BruchdehnungNom. Elongation at break [Mpa][Mpa] [%][%] 11 nicht erfindungsgemäßnot according to the invention 1 Schicht EUDRAGIT® FS1 coat EUDRAGIT ® FS 10,110.1 187187 22 nicht erfindungsgemäßnot according to the invention 1 Schicht EUDRAGIT® RL/RS (1:1)1 layer EUDRAGIT ® RL / RS (1: 1) 1,51.5 257257 44 nicht erfindungsgemäßnot according to the invention 1 Schicht EUDRAGIT® NE1 layer of EUDRAGIT ® NE 4,14.1 819819 55 nicht erfindungsgemäßnot according to the invention 1 Schicht Polyvinylacetat1 layer of polyvinyl acetate 10,010.0 450450 66 nicht erfindungsgemäß
(gemäß WO 01/68058)not according to the invention
(according to WO 01/68058) 1. Schicht: EUDRAGIT® RL/RS (1:1)1st layer: EUDRAGIT ® RL / RS (1: 1) 5,45.4 174174 2. Schicht EUDRAGIT® FS2nd layer EUDRAGIT ® FS 77 nicht erfindungsgemäßnot according to the invention 1. Schicht: Ethylcellulose1st layer: ethyl cellulose Nicht bestimmbar, weil sich die Schichten schon bei der Probenvorbereitung trennen.Not determinable because the layers separate during sample preparation. 2. Schicht EUDRAGIT® FS2nd layer EUDRAGIT ® FS 99 erfindungsgemäßinventively 1. Schicht EUDRAGIT® NE1st layer EUDRAGIT ® NE 7,07.0 174174 2. Schicht EUDRAGIT® FS2nd layer EUDRAGIT ® FS 1010 erfindungsgemäßinventively 1. Schicht Polyvinylacetat1st layer of polyvinyl acetate 8,08.0 288288 2. Schicht EUDRAGIT® FS2nd layer EUDRAGIT ® FS

Man erkennt aus den Messwerten, dass alle zweischichtigen Polymersysteme, die an sich gute Festigkeit einer EUDRAGIT® FS- Schicht reduzieren. Besonders stark ist dieser Effekt bei der Kombination gemäß WO 01/68058 , Beispiel 6.It can be seen from the measured values that all the two-layered polymer systems that reduce se good strength of an EUDRAGIT ® FS layer. This effect is particularly strong in the combination according to WO 01/68058 Example 6.

Rasterelekronenmikroskopische Aufnahmen von Querschnitten der Filme zeigen für alle erfindungsgemäßen, doppelschichtigen Filme homogene, gleichmäßige Schichten mit guter Haftung an der Grenzfläche.Scanning electron micrographs of cross sections of the films show homogeneous, uniform layers with good adhesion at the interface for all double-layer films according to the invention.

Claims (14)

  1. A multilayer pharmaceutical form comprising
    a) a core with an active pharmaceutical ingredient
    b) an inner coating which consists of 50 to 95% by weight of a (co)polymer which is composed of 95 to 100% by weight of free-radical-polymerized vinylic monomers having neutral side groups and 0 to 5% by weight of monomers having anionic side groups,
    c) an outer coating of a copolymer which is composed of 75 to 95% by weight of free-radical-polymerized C1- to C4-alkyl esters of acrylic or of methacrylic acid and 5 to 25% by weight of (meth)acrylate monomers having an anionic group in the alkyl radical, where 5 to 30% by weight of pharmaceutically usual excipients are present,
    characterized in that
    the inner coating comprises 5 to 50% by weight of pharmaceutically usual excipients which are not pore formers, and pore formers are present only in amounts of less than 5% by weight.
  2. The pharmaceutical form as claimed in claim 1, characterized in that the inner coating comprises a (co)polymer which is composed of 95 to 100% by weight of free-radical-polymerized C1- to C4-alkyl esters of acrylic or of methacrylic acid and where appropriate 0 to 5% by weight of acrylic or methacrylic acid.
  3. The pharmaceutical form as claimed in claim 1, characterized in that the inner coating comprises a (co)polymer which is a polyvinyl acetate.
  4. The pharmaceutical form as claimed in one or more of claims 1 to 3, characterized in that the pharmaceutically usual excipients which may be present in the inner coating are selected from the substance classes of plasticizers, stabilizers, colorants, antioxidants, wetting agents, pigments, gloss agents, mold release agents, antitack agents, with the content of pore formers, in particular water-insoluble pore formers such as kaolin, calcium carbonate, calcium hydrogen phosphate, magnesium oxide, microcrystalline cellulose, titanium dioxide or iron oxide, and especially water-soluble pore formers such as povidone K30, polyvinyl alcohol, cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC), methylcellulose or sodium carboxymethylcellulose, sucrose, xylitol, sorbitol, mannitol, maltose, xylose, glucose, potassium chloride, sodium chloride, polysorbate 80, polyethylene glycol or sodium citrate, being zero or only amounts of less than 5% by weight.
  5. The pharmaceutical form as claimed in one or more of claims 1 to 4, characterized in that the total weight of the inner coating amounts to 2 to 50% by weight based on the total weight of the core.
  6. The pharmaceutical form as claimed in one or more of claims 1 to 5, characterized in that the total weight of the outer coating amounts to 5 to 50% by weight based on the total weight of the core and of the inner coating.
  7. The pharmaceutical form as claimed in one or more of claims 1 to 6, characterized in that the contained active pharmaceutical ingredient is an aminosalicylate, a sulfonamide or a glucocorticoid.
  8. The pharmaceutical form as claimed in claim 7, characterized in that the active pharmaceutical ingredient is 5-aminosalicylic acid, olsalazine, sulfasalazine, prednisone or budesonide.
  9. The pharmaceutical form as claimed in one or more of claims 1 to 6, characterized in that the active pharmaceutical ingredient is an enzyme, a peptide hormone, an immunomodulatory protein, an antigen or antibody.
  10. The pharmaceutical form as claimed in claim 5, characterized in that the active pharmaceutical ingredient is a pancreatin, an insulin, a human growth hormone (hGH), carboplatin, intron A, calcitonin, cromalyn, an interferon, granulocyte colony stimulating factor (G-CSF), an interleukin, parathyroid hormones, glucagon, pro-somatostatin, a somatostatin, detirelix, cetrorelix, vasopressin, 1-deaminocysteine-8-D-arginine-vasopressin, leuprolide acetate or an antigen which has been isolated from grasses or other plants such as, for example, rye, wheat, barley, oats, bermuda grass, horsetail, sycamore, elm, oak, plane tree, poplar, cedar, thistles.
  11. A process for producing a pharmaceutical form as claimed in one or more of claims 1 to 10, characterized by the steps
    a) production of a core having an active pharmaceutical ingredient by means of spray application to a neutral core (nonpareilles) or by rotagglomeration, precipitation, spray processes or extrusion and spheronization without a neutral core and subsequently
    b) application of the inner coating by spray application so that active ingredient-containing, coated pellets are obtained,
    c) application of the outer coating by spray application so that active ingredient-containing, doubly coated pellets are obtained,
    d) optionally a final curing treatment to stabilize the release profile, e.g. by storing in the dry at 40°C for 2 hours.
  12. The process as claimed in claim 11, characterized in that the resulting pellets are processed with the aid of pharmaceutically usual excipients and in a manner known per se to a multiparticulate pharmaceutical form, in particular to pellet-containing tablets, minitablets, capsules, sachets or reconstitutable powders which are formulated so that the contained pellets are released in the pH range of the stomach.
  13. The use of a pharmaceutical form as claimed in one or more of claims 1 to 10 as constituent of a multiparticulate pharmaceutical form.
  14. The use as claimed in claim 13 as constituent of compressed tablet, capsules, sachets or reconstitutable powders.
EP05746448A 2004-07-23 2005-05-18 Medicament in a multilayer form Active EP1781263B1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
SI200530505T SI1781263T1 (en) 2004-07-23 2005-05-18 Medicament in a multilayer form
PL05746448T PL1781263T3 (en) 2004-07-23 2005-05-18 Medicament in a multilayer form

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102004035936A DE102004035936A1 (en) 2004-07-23 2004-07-23 Multilayer dosage form
PCT/EP2005/005374 WO2006010394A2 (en) 2004-07-23 2005-05-18 Medicament in a multilayer form

Publications (2)

Publication Number Publication Date
EP1781263A2 EP1781263A2 (en) 2007-05-09
EP1781263B1 true EP1781263B1 (en) 2008-10-01

Family

ID=35786554

Family Applications (1)

Application Number Title Priority Date Filing Date
EP05746448A Active EP1781263B1 (en) 2004-07-23 2005-05-18 Medicament in a multilayer form

Country Status (15)

Country Link
US (1) US20100151010A1 (en)
EP (1) EP1781263B1 (en)
JP (1) JP5534643B2 (en)
KR (2) KR20070034067A (en)
CN (1) CN1972674B (en)
AT (1) ATE409464T1 (en)
BR (1) BRPI0513743B8 (en)
CA (1) CA2570277C (en)
DE (2) DE102004035936A1 (en)
ES (1) ES2314662T3 (en)
IL (1) IL180849A (en)
MX (1) MX2007000954A (en)
PL (1) PL1781263T3 (en)
SI (1) SI1781263T1 (en)
WO (1) WO2006010394A2 (en)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SG174026A1 (en) 2006-08-03 2011-09-29 Nitec Pharma Ag Delayed-release glucocorticoid treatment of rheumatoid disease
WO2009154810A2 (en) * 2008-02-25 2009-12-23 Dr. Reddy's Laboratories Ltd. Delivery systems for multiple active agents
JP5604304B2 (en) 2008-03-11 2014-10-08 武田薬品工業株式会社 Orally disintegrating solid preparation
EP2309999A1 (en) * 2008-06-26 2011-04-20 McNeil-PPC, Inc. Coated particles containing pharmaceutically active agents
US9795576B2 (en) * 2010-09-27 2017-10-24 Basf Se Protective coatings for acidic active ingredients
CA2936741C (en) 2014-10-31 2018-11-06 Purdue Pharma Methods and compositions particularly for treatment of attention deficit disorder
CN107708677B (en) 2015-06-05 2021-07-13 赢创运营有限公司 Pharmaceutical or health-care product composition resistant to influence of ethanol
US10328087B2 (en) 2015-07-23 2019-06-25 Therapeuticsmd, Inc. Formulations for solubilizing hormones
WO2017173071A1 (en) 2016-04-01 2017-10-05 Therapeuticsmd, Inc. Steroid hormone pharmaceutical composition
US10286077B2 (en) 2016-04-01 2019-05-14 Therapeuticsmd, Inc. Steroid hormone compositions in medium chain oils
CN107712706A (en) * 2017-09-27 2018-02-23 福建永生活力生物工程有限公司 Chlorella Rosa roxburghii composite sheet and preparation method thereof
US10722473B2 (en) 2018-11-19 2020-07-28 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0520119A1 (en) * 1991-06-17 1992-12-30 Spirig Ag Pharmazeutische Präparate New oral diclofenac composition
US5654004A (en) * 1992-11-06 1997-08-05 Hisamitsu Pharmaceutical Co., Inc. Oral pharmaceutical preparation releasable in the lower digestive tract
US5945124A (en) 1995-07-05 1999-08-31 Byk Gulden Chemische Fabrik Gmbh Oral pharmaceutical composition with delayed release of active ingredient for pantoprazole
DE10013029A1 (en) * 2000-03-17 2001-09-20 Roehm Gmbh Multilayer formulation for controlled drug release in colon, comprising drug-containing core having inner and outer coatings of acrylic copolymers with quaternary ammonium and anionic groups respectively
HU229291B1 (en) * 2001-01-31 2013-10-28 Evonik Roehm Gmbh Multi-particulate form of medicament, comprising at least two differently coated forms of pellet
US6827947B2 (en) * 2001-12-19 2004-12-07 Astrazeneca Ab Film coating
DE10214002A1 (en) * 2002-03-27 2003-10-09 Roehm Gmbh Pharmaceutical formulation for the active substance budesonide
DE10250543A1 (en) * 2002-10-29 2004-05-19 Röhm GmbH & Co. KG Multilayer dosage form

Also Published As

Publication number Publication date
DE502005005559D1 (en) 2008-11-13
EP1781263A2 (en) 2007-05-09
DE102004035936A1 (en) 2006-03-16
BRPI0513743B1 (en) 2018-05-15
CN1972674B (en) 2010-05-12
IL180849A0 (en) 2007-07-04
US20100151010A1 (en) 2010-06-17
MX2007000954A (en) 2007-04-16
JP5534643B2 (en) 2014-07-02
ES2314662T3 (en) 2009-03-16
BRPI0513743A (en) 2008-05-13
KR20130046448A (en) 2013-05-07
BRPI0513743B8 (en) 2021-05-25
SI1781263T1 (en) 2009-02-28
IL180849A (en) 2010-11-30
PL1781263T3 (en) 2009-04-30
KR101739166B1 (en) 2017-05-23
CN1972674A (en) 2007-05-30
CA2570277A1 (en) 2006-02-02
WO2006010394A2 (en) 2006-02-02
WO2006010394A3 (en) 2006-09-08
KR20070034067A (en) 2007-03-27
JP2008507482A (en) 2008-03-13
ATE409464T1 (en) 2008-10-15
CA2570277C (en) 2013-01-15

Similar Documents

Publication Publication Date Title
EP1781263B1 (en) Medicament in a multilayer form
EP1178781B1 (en) Multilayer pharmaceutical product for release in the colon
EP1478352B1 (en) Pharmaceutical dosage form and method for the production thereof
EP1496870B1 (en) Dosage form and method for producing the same
EP1117387B1 (en) Coated medicament forms with controlled active substance release
EP1487421B1 (en) Pharmaceutical formulation for the active ingredient budesonide
DE19940944B4 (en) Retarded, oral, pharmaceutical dosage forms
EP0519870B1 (en) New oral diclofenac composition
EP0955041B1 (en) Aqueous dispersion useful for the production of coating and binding means for oral solid medicament
SK9132003A3 (en) A film coating composition, a coating film, pharmaceutical formulation comprising same and a process for its production
EP3223797B1 (en) Pharmaceutical or nutraceutical composition with resistance against the influence of ethanol
WO2002060415A1 (en) Multi-particulate form of medicament, comprising at least two differently coated forms of pellet
EP1435922A1 (en) Use of a copolymer to produce a galenic form containing a peptide or a protein as active agent
DE60035579T2 (en) MULTIPARTICELY MEDICAMENT COMPOSITIONS WITH A CONTROLLED ACTIVE INGREDIENT DELIVERING SELECTIVE INHIBITORS OF SEROTONIN RECOVERY
WO2001068057A1 (en) Use of a copolymer for producing a pharmaceutical product for the therapy of ulcerative colitis, and pharmaceutical product provided for the inventive use

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20061101

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU MC NL PL PT RO SE SI SK TR

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20070605

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: EVONIK ROEHM GMBH

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU MC NL PL PT RO SE SI SK TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

Free format text: NOT ENGLISH

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

Free format text: LANGUAGE OF EP DOCUMENT: GERMAN

REF Corresponds to:

Ref document number: 502005005559

Country of ref document: DE

Date of ref document: 20081113

Kind code of ref document: P

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

REG Reference to a national code

Ref country code: GR

Ref legal event code: EP

Ref document number: 20080403616

Country of ref document: GR

RAP2 Party data changed (patent owner data changed or rights of a patent transferred)

Owner name: EVONIK ROEHM GMBH

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2314662

Country of ref document: ES

Kind code of ref document: T3

NLT2 Nl: modifications (of names), taken from the european patent patent bulletin

Owner name: EVONIK ROEHM GMBH

Effective date: 20090121

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20081001

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20090101

REG Reference to a national code

Ref country code: PL

Ref legal event code: T3

REG Reference to a national code

Ref country code: HU

Ref legal event code: AG4A

Ref document number: E004805

Country of ref document: HU

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20090201

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20081001

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20090302

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20081001

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20081001

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20081001

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20081001

26N No opposition filed

Effective date: 20090702

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20090531

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20090518

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20081001

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 11

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 12

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 13

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 14

REG Reference to a national code

Ref country code: DE

Ref legal event code: R081

Ref document number: 502005005559

Country of ref document: DE

Owner name: EVONIK OPERATIONS GMBH, DE

Free format text: FORMER OWNER: EVONIK ROEHM GMBH, 64293 DARMSTADT, DE

REG Reference to a national code

Ref country code: HU

Ref legal event code: GB9C

Owner name: EVONIK OPERATIONS GMBH, DE

Free format text: FORMER OWNER(S): EVONIK ROEHM GMBH, DE

REG Reference to a national code

Ref country code: CH

Ref legal event code: PUE

Owner name: EVONIK OPERATIONS GMBH, DE

Free format text: FORMER OWNER: EVONIK ROEHM GMBH, DE

REG Reference to a national code

Ref country code: GB

Ref legal event code: 732E

Free format text: REGISTERED BETWEEN 20200702 AND 20200708

REG Reference to a national code

Ref country code: BE

Ref legal event code: HC

Owner name: EVONIK OPERATIONS GMBH; DE

Free format text: DETAILS ASSIGNMENT: CHANGE OF OWNER(S), CHANGEMENT DE NOM DU PROPRIETAIRE

Effective date: 20200525

Ref country code: BE

Ref legal event code: PD

Owner name: EVONIK DEGUSSA GMBH; DE

Free format text: DETAILS ASSIGNMENT: CHANGE OF OWNER(S), CESSION

Effective date: 20200525

REG Reference to a national code

Ref country code: NL

Ref legal event code: HC

Owner name: EVONIK OPERATIONS GMBH; DE

Free format text: DETAILS ASSIGNMENT: CHANGE OF OWNER(S), CHANGE OF OWNER(S) NAME

Effective date: 20200921

Ref country code: NL

Ref legal event code: PD

Owner name: EVONIK DEGUSSA GMBH; DE

Free format text: DETAILS ASSIGNMENT: CHANGE OF OWNER(S), ASSIGNMENT

Effective date: 20200921

REG Reference to a national code

Ref country code: SK

Ref legal event code: PC4A

Ref document number: E 4583

Country of ref document: SK

Owner name: EVONIK DEGUSSA GMBH, ESSEN, DE

Free format text: FORMER OWNER: ROEHM GMBH, DARMSTADT, DE

Effective date: 20201021

Ref country code: SK

Ref legal event code: TC4A

Ref document number: E 4583

Country of ref document: SK

Owner name: EVONIK OPERATIONS GMBH, ESSEN, DE

Effective date: 20201021

REG Reference to a national code

Ref country code: AT

Ref legal event code: PC

Ref document number: 409464

Country of ref document: AT

Kind code of ref document: T

Owner name: EVONIK OPERATIONS GMBH, DE

Effective date: 20201124

REG Reference to a national code

Ref country code: SI

Ref legal event code: SP73

Owner name: EVONIK ROEHM GMBH; DE

Effective date: 20210112

REG Reference to a national code

Ref country code: ES

Ref legal event code: PC2A

Owner name: EVONIK OPERATIONS GMBH

Effective date: 20210422

REG Reference to a national code

Ref country code: SI

Ref legal event code: SP73

Owner name: EVONIK OPERATIONS GMBH; DE

Effective date: 20210315

P01 Opt-out of the competence of the unified patent court (upc) registered

Effective date: 20230526

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 20230519

Year of fee payment: 19

Ref country code: IT

Payment date: 20230526

Year of fee payment: 19

Ref country code: IE

Payment date: 20230522

Year of fee payment: 19

Ref country code: FR

Payment date: 20230525

Year of fee payment: 19

Ref country code: DE

Payment date: 20230519

Year of fee payment: 19

Ref country code: CH

Payment date: 20230605

Year of fee payment: 19

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: TR

Payment date: 20230516

Year of fee payment: 19

Ref country code: SK

Payment date: 20230511

Year of fee payment: 19

Ref country code: SI

Payment date: 20230504

Year of fee payment: 19

Ref country code: SE

Payment date: 20230519

Year of fee payment: 19

Ref country code: PL

Payment date: 20230505

Year of fee payment: 19

Ref country code: HU

Payment date: 20230523

Year of fee payment: 19

Ref country code: GR

Payment date: 20230522

Year of fee payment: 19

Ref country code: AT

Payment date: 20230522

Year of fee payment: 19

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 20230519

Year of fee payment: 19

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20230523

Year of fee payment: 19

Ref country code: ES

Payment date: 20230724

Year of fee payment: 19